Pyridone amides as modulators of sodium channels

ABSTRACT

The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/107,109, filed Aug. 21, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/667,722, filed Aug. 3, 2017, which is acontinuation of U.S. patent application Ser. No. 15/174,896, filed Jun.6, 2016, which is a continuation of U.S. patent application Ser. No.14/699,437, filed Apr. 29, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/167,759, filed Jan. 29, 2014, which claims thebenefit of U.S. Provisional Patent Application No. 61/759,059, filedJan. 31, 2013, all of which are incorporated herein by reference intheir entireties.

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds useful as inhibitors of sodiumchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders includingpain.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Neuropathic pain is a form of chronic pain caused by an injury to thesensory nerves (Dieleman, J. P., et al., Incidence rates and treatmentof neuropathic pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories,pain caused by generalized metabolic damage to the nerve and pain causedby a discrete nerve injury. The metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy.Discrete nerve injuries indications include post amputation pain,post-surgical nerve injury pain, and nerve entrapment injuries likeneuropathic back pain.

Voltage-gated sodium channels (Na_(V)'s) play a critical role in painsignaling. Na_(V)'s are key biological mediators of electrical signalingas they are the primary mediators of the rapid upstroke of the actionpotential of many excitable cell types (e.g. neurons, skeletal myocytes,cardiac myocytes). The evidence for the role of these channels in normalphysiology, the pathological states arising from mutations in sodiumchannel genes, preclinical work in animal models, and the clinicalpharmacology of known sodium channel modulating agents all point to thecentral role of Na_(V)'s in pain sensation (Rush, A. M. and T. R.Cummins, Painful Research: Identification of a Small-Molecule Inhibitorthat Selectively Targets Na _(V)1.8 Sodium Channels. Mol Interv, 2007.7(4): p. 192-5); England, S., Voltage-gated sodium channels: the searchfor subtype-selective analgesics. Expert Opin Investig Drugs 17 (12), p.1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels andnociception: recent concepts and therapeutic opportunities. Curr OpinPharmacol 8 (1), p. 50-56 (2008)). Na_(V)'s are the primary mediators ofthe rapid upstroke of the action potential of many excitable cell types(e.g. neurons, skeletal myocytes, cardiac myocytes), and thus arecritical for the initiation of signaling in those cells (Hille, Bertil,Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates,Inc., Sunderland, Mass., 2001)). Because of the role Na_(V)'s play inthe initiation and propagation of neuronal signals, antagonists thatreduce Na_(V) currents can prevent or reduce neural signaling and Na_(V)channels have long been considered likely targets to reduce pain inconditions where hyper-excitability is observed (Chahine, M., Chatelier,A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels inneurological disorders. CNS Neurol Disord Drug Targets 7 (2), p. 144-58(2008)). Several clinically useful analgesics have been identified asinhibitors of Na_(V) channels. The local anesthetic drugs such aslidocaine block pain by inhibiting Na_(V) channels, and other compounds,such as carbamazepine, lamotrigine, and tricyclic antidepressants thathave proven effective at reducing pain have also been suggested to actby sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects oftheir mechanisms of action. Eur J Pain 6 Suppl A, p. 3-9 (2002); Wang,G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na⁺currents by antidepressant sertraline and paroxetine. J Membr Biol 222(2), p. 79-90 (2008)).

The Na_(V)'s form a subfamily of the voltage-gated ion channelsuper-family and comprises 9 isoforms, designated Na_(V)1.1-Na_(V)1.9.The tissue localizations of the nine isoforms vary greatly. Na_(V)1.4 isthe primary sodium channel of skeletal muscle, and Na_(V)1.5 is primarysodium channel of cardiac myocytes. Na_(V)'s 1.7, 1.8 and 1.9 areprimarily localized to the peripheral nervous system, while Na_(V)'s1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the centraland peripheral nervous systems. The functional behaviors of the nineisoforms are similar but distinct in the specifics of theirvoltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L.,and Waxman, S. G., International Union of Pharmacology. XLVII.Nomenclature and structure-function relationships of voltage-gatedsodium channels. Pharmacol Rev 57 (4), p. 397 (2005)).

Immediately upon their discovery, Na_(V)1.8 channels were identified aslikely targets for analgesia (Akopian, A. N., L. Sivilotti, and J. N.Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed bysensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then,Na_(V)1.8 has been shown to be the most significant carrier of thesodium current that maintains action potential firing in small DRGneurons (Blair, N. T. and B. P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na+ current, TTX-resistant Na⁺ current, and Ca²⁺ currentin the action potentials of nociceptive sensory neurons. J Neurosci.,2002. 22(23): p. 10277-90). Na_(V)1.8 is essential for spontaneousfiring in damaged neurons, like those that drive neuropathic pain (Roza,C., et al., The tetrodotoxin-resistant Na⁺ channel Na_(V)1.8 isessential for the expression of spontaneous activity in damaged sensoryaxons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M. F., etal., A-803467, a potent and selective Na_(V)1.8 sodium channel blocker,attenuates neuropathic and inflammatory pain in the rat. Proc Natl AcadSci. USA, 2007. 104(20): p. 8520-5; Joshi, S. K., et al., Involvement ofthe TTX-resistant sodium channel Na_(V)1.8 in inflammatory andneuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2):pp. 75-82; Lai, J., et al., Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, Na_(V)1.8.Pain, 2002. 95(1-2): p. 143-52; Dong, X. W., et al., Small interferingRNA-mediated selective knockdown of Na(_(V))1.8 tetrodotoxin-resistantsodium channel reverses mechanical allodynia in neuropathic rats.Neuroscience, 2007. 146(2): p. 812-21; Huang, H. L., et al., Proteomicprofiling of neuromas reveals alterations in protein composition andlocal protein synthesis in hyper-excitable nerves. Mol Pain, 2008. 4: p.33; Black, J. A., et al., Multiple sodium channel isoforms andmitogen-activated protein kinases are present in painful human neuromas.Ann Neurol, 2008. 64(6): p. 644-53; Coward, K., et al.,Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human painstates. Pain, 2000. 85(1-2): p. 41-50; Yiangou, Y., et al., SNS/PN3 andSNS2/NaN sodium channel-like immunoreactivity in human adult and neonateinjured sensory nerves. FEBS Lett, 2000. 467(2-3): p. 249-52; Ruangsri,S., et al., Relationship of axonal voltage-gated sodium channel 1.8(Na_(V)1.8) mRNA accumulation to sciatic nerve injury-induced painfulneuropathy in rats. J Biol Chem. 286(46): p. 39836-47). The small DRGneurons where Na_(V)1.8 is expressed include the nociceptors criticalfor pain signaling. Na_(V)1.8 is the primary channel that mediates largeamplitude action potentials in small neurons of the dorsal root ganglia(Blair, N. T. and B. P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na⁺current, TTX-resistant Na⁺ current, and Ca²⁺ current in the actionpotentials of nociceptive sensory neurons. J Neurosci., 2002. 22(23): p.10277-90). Na_(V)1.8 is necessary for rapid repetitive action potentialsin nociceptors, and for spontaneous activity of damaged neurons. (Choi,J. S. and S. G. Waxman, Physiological interactions between Na_(V)1.7 andNa_(V)1.8 sodium channels: a computer simulation study. J Neurophysiol.106(6): p. 3173-84; Renganathan, M., T. R. Cummins, and S. G. Waxman,Contribution of Na(_(V))1.8 sodium channels to action potentialelectrogenesis in DRG neurons. J Neurophysiol., 2001. 86(2): p. 629-40;Roza, C., et al., The tetrodotoxin-resistant Na⁺ channel Na_(V)1.8 isessential for the expression of spontaneous activity in damaged sensoryaxons of mice. J Physiol., 2003. 550(Pt 3): p. 921-6). In depolarized ordamaged DRG neurons, Na_(V)1.8 appears to be the primary driver ofhyper-excitablility (Rush, A. M., et al., A single sodium channelmutation produces hyper- or hypoexcitability in different types ofneurons. Proc Natl Acad Sci USA, 2006. 103(21): p. 8245-50). In someanimal pain models, Na_(V)1.8 mRNA expression levels have been shown toincrease in the DRG (Sun, W., et al., Reduced conduction failure of themain axon of polymodal nociceptive C-fibres contributes to painfuldiabetic neuropathy in rats. Brain. 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of NaV1.7, Na_(V)1.8 and Na_(V)1.9in a distinct population of dorsal root ganglia innervating the rat kneejoint in a model of chronic inflammatory joint pain. Eur J Pain, 2008.12(5): p. 564-72; Qiu, F., et al., Increased expression oftetrodotoxin-resistant sodium channels Na_(V)1.8 and Na_(V)1.9 withindorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett.512(2): p. 61-6).

The primary drawback to the known Na_(V) inhibitors is their poortherapeutic window, and this is likely a consequence of their lack ofisoform selectivity. Since Na_(V)1.8 is primarily restricted to theneurons that sense pain, selective Na_(V)1.8 blockers are unlikely toinduce the adverse events common to non-selective Na_(V) blockers.Accordingly, there remains a need to develop additional Na_(V) channelantagonists preferably those that are more Na_(V)1.8 selective and morepotent with increased metabolic stability and with fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels. These compounds have thegeneral formula I or I′:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, chronic pain,gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of formula I or I′

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:

G is

X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—;R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—;R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—;R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);R⁸ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry,”Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry,” 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention can optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. As described herein, the variables R¹-R⁹in formula I or I′ encompass specific groups, such as, for example,alkyl and cycloalkyl. As one of ordinary skill in the art willrecognize, combinations of substituents envisioned by this invention arethose combinations that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The phrase “optionally substituted” may be used interchangeably with thephrase “substituted or unsubstituted.” In general, the term“substituted,” whether preceded by the term “optionally” or not, refersto the replacement of hydrogen radicals in a given structure with theradical of a specified substituent. Specific substituents are describedabove in the definitions and below in the description of compounds andexamples thereof. Unless otherwise indicated, an optionally substitutedgroup can have a substituent at each substitutable position of thegroup, and when more than one position in any given structure can besubstituted with more than one substituent selected from a specifiedgroup, the substituent can be either the same or different at everyposition. A ring substituent, such as a heterocycloalkyl, can be boundto another ring, such as a cycloalkyl, to form a spiro-bicyclic ringsystem, e.g., both rings share one common atom. As one of ordinary skillin the art will recognize, combinations of substituents envisioned bythis invention are those combinations that result in the formation ofstable or chemically feasible compounds.

The phrase “up to,” as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 4” means any one of 0, 1, 2, 3, and 4.

The term “aliphatic,” “aliphatic group” or “alkyl” as used herein, meansa straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups.

The terms “cycloaliphatic” or “cycloalkyl” mean a monocyclic hydrocarbonring, or a polycyclic hydrocarbon ring system that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic and has a single point of attachment to the rest of themolecule. The term “polycyclic ring system,” as used herein, includesbicyclic and tricyclic 4- to 12-membered structures that form at leasttwo rings, wherein the two rings have at least one atom in common (e.g.,2 atoms in common) including fused, bridged, or spirocyclic ringsystems.

The term “halogen” or “halo” as used herein, means F, Cl, Br or I.Unless otherwise specified, the term “heterocycle,” “heterocyclyl,”“heterocycloaliphatic,” “heterocycloalkyl,” or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic, or tricyclic ringsystems in which one or more ring atoms in one or more ring members isan independently selected heteroatom. Heterocyclic ring can be saturatedor can contain one or more unsaturated bonds. In some embodiments, the“heterocycle,” “heterocyclyl,” “heterocycloaliphatic,”“heterocycloalkyl,” or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring.”

The term “heteroaryl,” used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy,” refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic.”

“D” and “d” both refer to deuterium.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Thus, included within the scope of the invention aretautomers of compounds of formula I and I′. The structures also includezwitterionic forms of the compounds or salts of formula I and formula I′where appropriate.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched or isotopically-labeled atoms. Theisotopically-labeled compounds may have one or more atoms replaced by anatom having an atomic mass or mass number usually found in nature.Examples of isotopes present in compounds of formula I and formula I′include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³⁵S and ¹⁸F. Certain isotopically-labeled compounds offormula I or formula I′, in addition to being useful as therapeuticagents, are also useful in drug and/or substrate tissue distributionassays, as analytical tools or as probes in other biological assays. Inone aspect of the present invention, tritiated (e.g., ³H) and carbon-14(e.g., ¹⁴C) isotopes are useful given their ease of detectability. Inanother aspect of the present invention, replacement of one or morehydrogen atoms with heavier isotopes such as deuterium, (e.g., ²H) canafford certain therapeutic advantages.

In the formulas and drawings, a line transversing a ring and bonded toan R group such as in

means that the R group, i.e. the R⁸ group can be bonded to any carbon ofthat ring as valency allows.

Within a definition of a term as, for example, X, R^(X), R¹, R², R³, R⁴,R⁸, or R⁹ when a CH₂ unit or, interchangeably, methylene unit may bereplaced by —O—, it is meant to include any CH₂ unit, including a CH₂within a terminal methyl group. For example, CH₂CH₂CH₂OH is within thedefinition of C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units maybe replaced by —O-because the CH₂ unit of the terminal methyl group hasbeen replaced by —O—.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

wherein:R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

wherein:R⁵ is H or —X—R^(X);R^(5′) is H or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R⁷ is H or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment R⁵ is H. In another embodiment, R⁵ is halogen. Inanother embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is —X—R^(X). Inanother embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment R^(5′) is H. In another embodiment, R^(5′) is halogen.In another embodiment, R^(5′) is Cl. In another embodiment, R^(5′) is F.In another embodiment, R^(5′) is CN. In another embodiment, R^(5′) is—X—R^(X). In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen. In another embodiment, R^(5′) is CH₃. In anotherembodiment, R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. Inanother embodiment, R¹ is OCH₃. In another embodiment, R^(5′) is CH₂OH.In another embodiment, R^(5′) is OCF₃. In another embodiment, R^(5′) isOCHF₂.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is —X—R^(X). Inanother embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment R⁶ is H. In another embodiment, R⁶ is halogen. Inanother embodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH3. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment, R^(6′) is H. In another embodiment, R^(6′) ishalogen. In another embodiment, R^(6′) is Cl. In another embodiment,R^(6′) is F. In another embodiment, R^(6′) is CN. In another embodiment,R^(6′) is —X—R^(X). In another embodiment, R^(6′) is —X—R^(X) whereinR^(X) is absent. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X)is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R^(6′) is CH₃. In anotherembodiment, R^(6′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is halogen. Inanother embodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment, R⁷ is H In another embodiment, R⁷ is —X—R^(X). Inanother embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R¹ is OCH₃, OCH₂CH₃OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit of saidC₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈ cycloaliphatic andsaid C₃-C₈ cycloaliphatic is substituted with up 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, R⁷ is—X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is

wherein:X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is absent. In another embodiment, X isCH₂CH₂CH(CH₃)₃ or CH₂CH(CH₃)₂ and R^(X) is absent. In anotherembodiment, X is CH₂CH₂CH₂CF₃ or CH₂CH₂CF₃ and R^(X) is absent.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is —X—R^(X) wherein X is abond and R^(X) is C₃-C₈ cycloaliphatic wherein up to two non-adjacentCH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O— and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, X is a bond and R^(X) iscyclobutane, cyclohexane, bicyclo[2.2.1]heptane, orbicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O—; and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic. In another embodiment, X is CH₂ andR^(X) is cyclopropyl or cyclopentyl. In another embodiment, X is CH₂ andR^(X) is C₃-C₈ cycloaliphatic with up to 3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, X is CH₂ and R^(X) is1-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl arereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic wherein one CH₂ unit of said C₃-C₈cycloaliphatic is replaced with —O—. In another embodiment, X is CH₂ andR^(X) is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I orI′ and the attendant definitions, wherein G is —X—R^(X) and —X—R^(X) isselected from:

In another aspect, the invention provides a compound of formula I-A orI′-A:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:

G is

X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);R⁸ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

wherein:R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

wherein:R⁵ is H, or —X—R^(X);R^(5′) is H, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R⁷ is H, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is halogen. Inanother embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is —X—R^(X). Inanother embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, G is

In one embodiment R^(5′) is H. In another embodiment, R^(5′) is halogen.In another embodiment, R^(5′) is Cl. In another embodiment, R^(5′) is F.In another embodiment, R^(5′) is CN. In another embodiment, R^(5′) is—X—R^(X). In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen. In another embodiment, R^(5′) is CH₃. In anotherembodiment, R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R⁵ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. In anotherembodiment, R^(5′) is OCH₃. In another embodiment, R⁵ is CH₂OH. Inanother embodiment, R^(5′) is OCF₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, G is

In one embodiment R^(5′) is H. In another embodiment, R^(5′) is—X—R^(X). In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen. In another embodiment, R^(5′) is CH₃. In anotherembodiment, R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. Inanother embodiment, R^(5′) is OCH₃. In another embodiment, R^(5′) isCH₂OH. In another embodiment, R^(5′) is OCF₃. In another embodiment,R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R⁶ is H. In another embodiment, R⁶ is halogen. Inanother embodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R^(6′) is H. In another embodiment, R^(6′) ishalogen. In another embodiment, R^(6′) is Cl. In another embodiment,R^(6′) is F. In another embodiment, R^(6′) is CN. In another embodiment,R^(6′) is —X—R^(X). In another embodiment, R^(6′) is —X—R^(X) whereinR^(X) is absent. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X)is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R^(6′) is CH₃. In anotherembodiment, R^(6′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is halogen. Inanother embodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is —X—R^(X). Inanother embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit of saidC₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈ cycloaliphatic andsaid C₃-C₈ cycloaliphatic is substituted with 0-3 substituents selectedfrom halogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X)wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is

wherein:X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is absent. In another embodiment, X isCH₂CH₂CH(CH₃)₃ or CH₂CH(CH₃)₂ and R^(X) is absent. In anotherembodiment, X is CH₂CH₂CH₂CF₃ or CH₂CH₂CF₃ and R^(X) is absent.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is abond and R^(X) is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, orbicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O—; and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic. In another embodiment, X is CH₂ andR^(X) is cyclopropyl or cyclopentyl. In another embodiment, X is CH₂ andR^(X) is C₃-C₈ cycloaliphatic with up to 3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, X is CH₂ and R^(X) is1-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl arereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic wherein one CH₂ unit of said C₃-C₈cycloaliphatic is replaced with —O—. In another embodiment, X is CH₂ andR^(X) is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-Aor I′-A and the attendant definitions, wherein G is —X—R^(X) and—X—R^(X) is selected from:

In another aspect, the invention provides a compound of formula I-B orI′-B:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:

G is

X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);R⁸ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃. In another embodiment, p is aninteger from 1 to 3 and R⁸ is D.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

wherein:R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

wherein:R⁵ is H, or —X—R^(X);R^(5′) is H, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R⁷ is H, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two nono-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is halogen. Inanother embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, RI is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is CD₃. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R⁵is OCH₃, OCH₂CH₃ or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. Inanother embodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. Inanother embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is —X—R^(X). Inanother embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is CD₃. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R⁵is OCH₃, OCH₂CH₃ or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. Inanother embodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. Inanother embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R^(5′) is H. In another embodiment, R^(5′) is D. Inanother embodiment, R^(5′) is halogen. In another embodiment, R^(5′) isCl. In another embodiment, R^(5′) is F. In another embodiment, R^(5′) isCN. In another embodiment, R^(5′) is —X—R^(X). In another embodiment,R^(5′) is —X—R^(X) wherein R^(X) is absent. In another embodiment,R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R^(5′) is CH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X)is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R^(5′) is OCH₃, OCH₂CH₃ or OCH(CH₃)₂.In another embodiment, R^(5′) is OCH₃. In another embodiment, R^(5′) isCH₂OH. In another embodiment, R^(5′) is OCF₃. In another embodiment,R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R^(5′) is H. In another embodiment, R^(5′) is D. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃ or OCH(CH₃)₂. In anotherembodiment, R^(5′) is OCH₃. In another embodiment, R^(5′) is CH₂OH. Inanother embodiment, R^(5′) is OCF₃. In another embodiment, R^(5′) isOCHF₂.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R⁶ is H. In another embodiment, R⁶ is D. In anotherembodiment, R⁶ is halogen. In another embodiment, R⁶ is Cl. In anotherembodiment, R⁶ is F. In another embodiment, R⁶ is CN. In anotherembodiment, R⁶ is —X—R^(X). In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen. In another embodiment, R⁶ is CH₃. Inanother embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. Inanother embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R^(6′) is H. In another embodiment, R^(6′) ishalogen. In another embodiment, R^(6′) is D. In another embodiment,R^(6′) is Cl. In another embodiment, R^(6′) is F. In another embodiment,R^(6′) is CN. In another embodiment, R^(6′) is —X—R^(X). In anotherembodiment, R^(6′) is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R^(6′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R^(6′) is CH₃. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is halogen. Inanother embodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is —X—R^(X). Inanother embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen and wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈ cycloaliphaticand said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, R⁷ is—X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is selected from:

In another embodiment, the invention features a compound of formula I-Bor I′-B the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is

wherein:X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is absent. In another embodiment, X isCH₂CH₂C(CH₃)₃ or CH₂CH(CH₃)₂ and R^(X) is absent. In another embodiment,X is CH₂CH₂CH₂CF₃ or CH₂CH₂CF₃ and R^(X) is absent.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is abond and R^(X) is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, orbicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O—; and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic. In another embodiment, X is CH₂ andR^(X) is cyclopropyl or cyclopentyl. In another embodiment, X is CH₂ andR^(X) is C₃-C₈ cycloaliphatic with up to 3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, X is CH₂ and R^(X) is1-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl arereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic wherein one CH₂ unit of said C₃-C₈cycloaliphatic is replaced with —O—. In another embodiment, X is CH₂ andR^(X) is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-Bor I′-B and the attendant definitions, wherein G is selected from:

In another aspect, the invention provides a compound of formula I-C orI′-C:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:

G is

X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);R⁸ is halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

wherein:R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

wherein:R⁵ is H, or —X—R^(X);R^(5′) is H, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R⁷ is H, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is halogen. Inanother embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, RI is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment R⁵ is H. In another embodiment, R⁵ is —X—R^(X). Inanother embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, RI is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment R^(5′) is H. In another embodiment, R^(5′) is halogen.In another embodiment, R^(5′) is Cl. In another embodiment, R^(5′) is F.In another embodiment, R^(5′) is CN. In another embodiment, R^(5′) is—X—R^(X). In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen. In another embodiment, R^(5′) is CH₃. In anotherembodiment, R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. Inanother embodiment, R¹ is OCH₃. In another embodiment, R^(5′) is CH₂OH.In another embodiment, R^(5′) is OCF₃. In another embodiment, R^(5′) isOCHF₂.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment R^(5′) is H. In another embodiment, R^(5′) is halogen.In another embodiment, R^(5′) is Cl. In another embodiment, R^(5′) is F.In another embodiment, R^(5′) is CN. In another embodiment, R^(5′) is—X—R^(X). In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen. In another embodiment, R^(5′) is CH₃. In anotherembodiment, R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R⁵ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. In anotherembodiment, R^(5′) is OCH₃. In another embodiment, R^(5′) is CH₂OH. Inanother embodiment, R^(5′) is OCF₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment, R⁶ is H. In another embodiment, R⁶ is halogen. Inanother embodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In another embodiment, R⁶ is H. In another embodiment, R^(6′) ishalogen. In another embodiment, R^(6′) is Cl. In another embodiment,R^(6′) is F. In another embodiment, R^(6′) is CN. In another embodiment,R^(6′) is —X—R^(X). In another embodiment, R^(6′) is —X—R^(X) whereinR^(X) is absent. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X)is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R^(6′) is CH₃. In anotherembodiment, R^(6′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is halogen. Inanother embodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is —X—R^(X). Inanother embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit of saidC₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈ cycloaliphatic andsaid C₃-C₈ cycloaliphatic is substituted with 0-3 substituents selectedfrom halogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X)wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is

wherein:X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is absent. In another embodiment, X isCH₂CH₂C(CH₃)₃ or CH₂CH(CH₃)₂ and R^(X) is absent. In another embodiment,X is CH₂CH₂CH₂CF₃ or CH₂CH₂CF₃ and R^(X) is absent.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is abond and R^(X) is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, orbicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O—; and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic. In another embodiment, X is CH₂ andR^(X) is cyclopropyl or cyclopentyl. In another embodiment, X is CH₂ andR^(X) is C₃-C₈ cycloaliphatic with up to 3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, X is CH₂ and R^(X) is1-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl arereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic wherein one CH₂ unit of said C₃-C₈cycloaliphatic is replaced with —O—. In another embodiment, X is CH₂ andR^(X) is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-Cor I′-C and the attendant definitions, wherein G is selected from:

In another aspect, the invention provides a compound of formula I-D orI′-D:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:

G is

X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R¹ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);R⁸ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein R¹ is halogen. In anotherembodiment, R¹ is CN. In another embodiment, R¹ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, p is an integer from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

wherein:R⁵ is H, halogen, CN, or —X—R^(X);R^(5′) is H, halogen, CN, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R^(6′) is H, halogen, CN, or —X—R^(X);R⁷ is H, halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

wherein:R⁵ is H, or —X—R^(X);R^(5′) is H, or —X—R^(X);R⁶ is H, halogen, CN, or —X—R^(X);R⁷ is H, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is halogen. Inanother embodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R⁵ is H. In another embodiment, R⁵ is —X—R^(X). Inanother embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment R^(5′) is H. In another embodiment, R^(5′) is halogen.In another embodiment, R^(5′) is Cl. In another embodiment, R^(5′) is F.In another embodiment, R^(5′) is CN. In another embodiment, R^(5′) is—X—R^(X). In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen. In another embodiment, R^(5′) is CH₃. In anotherembodiment, R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R⁵ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. In anotherembodiment, R^(5′) is OCH₃. In another embodiment, R⁵ is CH₂OH. Inanother embodiment, R^(5′) is OCF₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment R^(5′) is H. In another embodiment, R^(5′) is—X—R^(X). In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen. In another embodiment, R^(5′) is CH₃. In anotherembodiment, R^(5′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. Inanother embodiment, R^(5′) is OCH₃. In another embodiment, R^(5′) isCH₂OH. In another embodiment, R^(5′) is OCF₃. In another embodiment,R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R⁶ is H. In another embodiment, R⁶ is halogen. Inanother embodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R^(6′) is H. In another embodiment, R^(6′) ishalogen. In another embodiment, R^(6′) is Cl. In another embodiment,R^(6′) is F. In another embodiment, R^(6′) is CN. In another embodiment,R^(6′) is —X—R^(X). In another embodiment, R^(6′) is —X—R^(X) whereinR^(X) is absent. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X)is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R^(6′) is CH₃. In anotherembodiment, R^(6′) is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is halogen. Inanother embodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R⁷ is H. In another embodiment, R⁷ is —X—R^(X). Inanother embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

In one embodiment, R⁷ is —X—R^(X) wherein X is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit of saidC₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈ cycloaliphatic andsaid C₃-C₈ cycloaliphatic is substituted with 0-3 substituents selectedfrom halogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X)wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is

wherein:X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; andR^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is absent. In another embodiment, X isCH₂CH₂C(CH₃)₃ or CH₂CH(CH₃)₂ and R^(X) is absent. In another embodiment,X is CH₂CH₂CH₂CF₃ or CH₂CH₂CF₃ and R^(X) is absent.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is abond and R^(X) is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, orbicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O—; and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic. In another embodiment, X is CH₂ andR^(X) is cyclopropyl or cyclopentyl. In another embodiment, X is CH₂ andR^(X) is C₃-C₈ cycloaliphatic with up to 3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, X is CH₂ and R^(X) is1-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl arereplaced with —O— and R^(X) is C₃-C₈ cycloaliphatic wherein up to twonon-adjacent CH₂ of said C₃-C₈ cycloaliphatic may be replaced with —O—and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl. In another embodiment, X is CH₂and R^(X) is C₃-C₈ cycloaliphatic wherein one CH₂ unit of said C₃-C₈cycloaliphatic is replaced with —O—. In another embodiment, X is CH₂ andR^(X) is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-Dor I′-D and the attendant definitions, wherein G is selected from:

In another aspect, the invention provides a compound of formula I-E orI′-E

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—;R⁵ is halogen, CN, or —X—R^(X);R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R¹ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Eor I′-E and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-F orI′-F:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—;R⁵ is halogen, CN, or —X—R^(X);R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is CD₃. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R⁵is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is CH₂OH. In another embodiment, R⁵ isOCF₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃. In another embodiment, p is aninteger from 1 to 3 and R⁸ is D.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-For I′-F and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-G orI′-G:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is halogen, CN, or —X—R^(X);R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R¹ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenand wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— andR^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic issubstituted with 0-3 substituents selected from halogen and C₁-C₄ alkyl.In another embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Gor I′-G and the attendant definitions wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-H orI′-H:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is halogen, CN, or —X—R^(X);R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein R¹ is halogen. In anotherembodiment, R¹ is CN. In another embodiment, R¹ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R¹ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Hor I′-H and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-J orI′-J:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is H, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Jor I′-J and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Jor I′-J and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Jor I′-J and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Jor I′-J and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Jor I′-J and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Jor I′-J and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Jor I′-J and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-K orI′-K:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Kor I′-K and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Kor I′-K and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Kor I′-K and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Kor I′-K and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Kor I′-K and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, wherein p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, wherein p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R⁸is CH₃.

In another embodiment, the invention features a compound of formula I-Kor I′-K and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Kor I′-K and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-L orI′-L:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Lor I′-L and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-M orI′-M:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is H, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein R¹ is halogen. In anotherembodiment, R¹ is CN. In another embodiment, R¹ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Mor I′-M and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-N orI′-N:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Nor I′-N and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Nor I′-N and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Nor I′-N and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Nor I′-N and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Nor I′-N and the attendant definitions, wherein ring C is selected from:

In another aspect, the invention provides a compound of formula I-O orI′-O:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Oor I′-O and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Oor I′-O and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Oor I′-O and the attendant definitions, wherein p is an integer from 1 to3 and R⁸ is halogen. In another embodiment, p is an integer from 1 to 3and R⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R⁸is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—. Inanother embodiment, p is an integer from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Oor I′-O and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Oor I′-O and the attendant definitions, wherein ring C is selected from:

In another aspect, the invention provides a compound of formula I-P orI′-P:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁵ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is H, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Por I′-P and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Por I′-P and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Por I′-P and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Por I′-P and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Por I′-P and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Por I′-P and the attendant definitions, wherein ring C is selected from:

In another aspect, the invention provides a compound of formula I-Q orI′-Q:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁶ is halogen, CN, or —X—R^(X);R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is H, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein R⁶ is halogen. In anotherembodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Qor I′-Q and the attendant definitions, wherein ring D is selected from:

In another aspect, the invention provides a compound of formula I-R orI′-R:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁶ is halogen, CN, or —X—R^(X);R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is H, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein R⁶ is halogen. In anotherembodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Ror I′-R and the attendant definitions, wherein ring D is selected from:

In another aspect, the invention provides a compound of formula I-S orI′-S:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R³ is halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—;R⁶ is halogen, CN, or —X—R^(X);R⁷ is halogen, CN, or —X—R^(X);X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—;R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl;R⁸ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen and wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—;p is an integer from 0 to 3 inclusive; andR⁹ is H, or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is CN. In another embodiment, R² is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R² is CF₃. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R² is OCF₃. Inanother embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is F. In anotherembodiment, R³ is CN. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is t-butyl. In another embodiment, R³ is CF₃. In another embodiment,R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein R⁶ is halogen. In anotherembodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is C₃-C₈ cycloaliphatic and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl. In another embodiment, R⁷ is —X—R^(X) wherein Xis a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein R⁷ is —X—R^(X) wherein Xis C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein p is zero. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is halogen. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is Cl. In anotherembodiment, p is an integer from 1 to 3 and R⁸ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, p is aninteger from 1 to 3 and R⁸ is CH₃.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein R⁹ is H. In anotherembodiment, R⁹ is C₁-C₆ alkyl. In another embodiment, R⁹ is CH₃. Inanother embodiment, R⁹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁹ is CH₂CH₂OH.

In another embodiment, the invention features a compound of formula I-Sor I′-S and the attendant definitions, wherein ring D is selected from:

In another embodiment, the invention features a compound of formula I orI′, wherein the compound or a pharmaceutically acceptable salt thereof,is selected from Table 1. Compounds names in Table 1 were generatedusing ChemBioDrawUltra version 12.0 from Cambridge Soft/Chem Office2010.

TABLE 1 Compound Numbers, Structures and Chemical Names

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

In one embodiment, the compound is4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound isN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound isN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound isN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound isN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

Salts, Compositions, Uses, Formulation, Administration and AdditionalAgents Pharmaceutically Acceptable Salts and Compositions

As discussed herein, the invention provides compounds that areinhibitors of voltage-gated sodium channels, and thus the presentcompounds are useful for the treatment of diseases, disorders, andconditions including, but not limited to chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia. Accordingly, in anotheraspect of the invention, pharmaceutically acceptable compositions areprovided, wherein these compositions comprise any of the compounds asdescribed herein, and optionally comprise a pharmaceutically acceptablecarrier, adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of inventioncan exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. According to theinvention, a pharmaceutically acceptable derivative includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to asubject in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitory active metabolite or residuethereof. As used herein, the term “inhibitorily active metabolite orresidue thereof” means that a metabolite or residue thereof is also aninhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical compositioncomprising the compound of the invention and a pharmaceuticallyacceptable carrier.

In another aspect, the invention features a pharmaceutical compositioncomprising a therapeutically effective amount of the compound or apharmaceutically acceptable salt thereof of the compounds of formula Ior formula I′ and one or more pharmaceutically acceptable carriers orvehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject a compound of formula I or formula I′ or a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof. Inanother aspect, the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia comprising administering aneffective amount of a compound, a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I orformula I′.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain wherein said method comprises administeringan effective amount of a compound, a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I orformula I′.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain, whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma;traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia wherein said methodcomprises administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I or formula I′.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain wherein said method comprisesadministering an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I or formula I′.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain or vulvodyniawherein said method comprises administering an effective amount of acompound, a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition of the compounds of formula I or formula I′.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain, whereinidiopathic pain comprises fibromyalgia pain wherein said methodcomprises administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I or formula I′.

In yet another aspect, the invention features a method wherein thesubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith an effective amount of a compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition of the compounds of formulaI or formula I′.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I or formula I′. In another aspect, the voltage-gated sodiumchannel is Nav1.8.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a biological sample comprisingcontacting the biological sample with an effective amount of a compound,a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition of the compounds of formula I or formula I′. In anotheraspect, the voltage-gated sodium channel is Nav1.8.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain, chronic pain,neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility, comprising administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I or formula I′.

In another aspect, the invention features a method of treating orlessening the severity in a subject of femur cancer pain; non-malignantchronic bone pain; rheumatoid arthritis; osteoarthritis; spinalstenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache; cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Toothneuropathy; hereditary sensory neuropathies; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury/exercise pain; acute visceral pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; chestpain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain,labor pain; cesarean section pain; acute inflammatory, burn and traumapain; acute intermittent pain, endometriosis; acute herpes zoster pain;sickle cell anemia; acute pancreatitis; breakthrough pain; orofacialpain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain indepression; leprosy pain; Behcet's disease pain; adiposis dolorosa;phlebitic pain; Guillain-Barre pain; painful legs and moving toes;Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladderand urogenital disease; urinary incontinence; hyperactivity bladder;painful bladder syndrome; interstitial cyctitis (IC); prostatitis;complex regional pain syndrome (CRPS), type I and type II; widespreadpain, paroxysmal extreme pain, pruritis, tinnitis, or angina-inducedpain, comprising administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I or formula I′.

In another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain comprisingadministering an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I or formula I′. In one aspect, the neuropathic pain isselected from post-herpetic neuralgia, diabetic neuralgia, painfulHIV-associated sensory neuropathy, trigeminal neuralgia, burning mouthsyndrome, post-amputation pain, phantom pain, painful neuroma, traumaticneuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis,carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsioninjury, brachial plexus avulsion, complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

Manufacture of Medicaments

In one aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in inhibiting a voltage-gated sodium channel. Inanother aspect, the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofchronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiacarrhythmia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofgut pain, wherein gut pain comprises inflammatory bowel disease pain,Crohn's disease pain or interstitial cystitis pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in a treating or lessening the severity in a subjectof neuropathic pain, wherein neuropathic pain comprises post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma;Morton's neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic neuropathy.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofmusculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention the invention provides the use of acompound or pharmaceutical composition described herein for themanufacture of a medicament for use in treating or lessening theseverity in a subject of inflammatory pain, wherein inflammatory paincomprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofidiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament in combination with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound or pharmaceutical composition.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of acute pain,chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders,psychiatric disorders, anxiety, depression, dipolar disorder, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of femur cancerpain; non-malignant chronic bone pain; rheumatoid arthritis;osteoarthritis; spinal stenosis; neuropathic low back pain; myofascialpain syndrome; fibromyalgia; temporomandibular joint pain; chronicvisceral pain, abdominal pain; pancreatic pain; IBS pain; chronic andacute headache pain; migraine; tension headache; cluster headaches;chronic and acute neuropathic pain, post-herpetic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain,renal colic pain, acute obstetric pain, labor pain; cesarean sectionpain; acute inflammatory, burn and trauma pain; acute intermittent pain,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dentalpain; multiple sclerosis (MS) pain; pain in depression; leprosy pain;Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barrepain; painful legs and moving toes; Haglund syndrome; erythromelalgiapain; Fabry's disease pain; bladder and urogenital disease; urinaryincontinence; hyperactivity bladder; painful bladder syndrome;interstitial cyctitis (IC); prostatitis; complex regional pain syndrome(CRPS), type I and type II; widespread pain, paroxysmal extreme pain,pruritis, tinnitis, or angina-induced pain.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of neuropathicpain. In one aspect, the neuropathic pain is selected from post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma, nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury,brachial plexus avulsion, complex regional pain syndrome, drug therapyinduced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

Administration of Pharmaceutically Acceptable Salts and Compositions.

In certain embodiments of the invention an “effective amount” of thecompound, a pharmaceutically acceptable salt thereof or pharmaceuticallyacceptable composition is that amount effective for treating orlessening the severity of one or more of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia.

The compounds and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of the pain or non-pain diseases recited herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the subject to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “subject” or “patient,” as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium channels. In one embodiment, thecompounds and compositions of the invention are inhibitors of Nav1.8 andthus, without wishing to be bound by any particular theory, thecompounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of Nav1.8 is implicated in the disease,condition, or disorder. When activation or hyperactivity of Nav1.8 isimplicated in a particular disease, condition, or disorder, the disease,condition, or disorder may also be referred to as a “Nav1.8-mediateddisease, condition or disorder.” Accordingly, in another aspect, theinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity ofNav1.8 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNav1.8 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the invention can be employed in combinationtherapies, that is, the compounds and pharmaceutically acceptablecompositions can be administered concurrently with, prior to, orsubsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.” For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blockade), neurosurgical (neurolysis ofCNS pathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, NineteenthEdition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & DohmeCorp., a subsidiary of Merck & Co., Inc., 2011, and the Food and DrugAdministration website, www.fda.gov, the entire contents of which arehereby incorporated by reference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

(1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl,cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine or pentazocine;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, metharbital, methohexital,pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal orthiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam ortriazolam;

(5) a histamine (Hi) antagonist having a sedative action, e.g.diphenhydramine, pyrilamine, promethazine, chlorpheniramine orchlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone ordichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,EN-3231 (MorphiDex®), a combination formulation of morphine anddextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or(−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,guanfacine, dexmedetomidine, modafinil, or4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine,amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine,topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g.(alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine,tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride,balaperidone, palindore, eplivanserin, osanetant, rimonabant,meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) orantagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HT_(1B/1D)agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan orrizatriptan;

(22) a 5-HT_(2A) receptor antagonist such asR(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol(MDL-100907);

(23) a cholinergic (nicotinic) analgesic, such as ispronicline(TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor, such as5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione(IC-351 or tadalafil),2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil),5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin--yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

(26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentinGR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®),3-methyl gabapentin,(1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate subtype 1 receptor (mGuR1) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertralinemetabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinedesmethyl metabolite), fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine and trazodone;

(30) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion,nomifensine and viloxazine (Vivalan®), especially a selectivenoradrenaline reuptake inhibitor such as reboxetine, in particular(S,S)-reboxetine;

(31) a dual serotonin-noradrenaline reuptake inhibitor, such asvenlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine(Cymbalta®), milnacipran and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such asS-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,NXN-462, or guanidinoethyldisulfide;

(33) an acetylcholinesterase inhibitor such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such asN-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin--yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamideor4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid;

(35) a leukotriene B4 antagonist; such as1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylicacid (CP-105696),5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valericacid (ONO-4057) or DPC-11870;

(36) a 5-lipoxygenase inhibitor, such as zileuton,6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone(ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone(CV-6504);

(37) a sodium channel blocker, such as lidocaine, lidocaine plustetracaine cream (ZRS-201) or eslicarbazepine acetate;

(38) an Na_(V)1.7 blocker, such as XEN-402 and such as those disclosedin WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613 orPCT/US2013/21535 the entire contents of each application herebyincorporated by reference.

(39) an Na_(V)1.8 blocker, such as those disclosed in WO2008/135826 andWO2006/011050 the entire contents of each application herebyincorporated by reference.

(40) a combined Na_(V)1.7 and Na_(V)1.8 blocker, such as DSP-2230 orBL-1021;

(41) a 5-HT3 antagonist, such as ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®,Qutenza®); and the pharmaceutically acceptable salts and solvatesthereof,

(43) a nicotinic receptor antagonist, such as varenicline;

(44) an N-type calcium channel antagonist, such as Z-160;

(45) a nerve growth factor antagonist, such as tanezumab;

(46)_an endopeptidase stimulant, such as senrebotase;

(47) an angiotensin II antagonist, such as EMA-401;

In one embodiment, the additional appropriate therapeutic agents areselected from V-116517, Pregabalin, controlled release Pregabalin,Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®),AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine(Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 orARC-4558.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. The amount of additional therapeutic agent in thepresently disclosed compositions will range from about 10% to 100% ofthe amount normally present in a composition comprising that agent asthe only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. In still another aspect,the invention includes an implantable device coated with a compositioncomprising a compound of the invention as described generally above, andin classes and subclasses herein, and a carrier suitable for coatingsaid implantable device. Suitable coatings and the general preparationof coated implantable devices are described in U.S. Pat. Nos. 6,099,562;5,886,026; and 5,304,121. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na_(V)1.8 activityin a biological sample or a subject, which method comprisesadministering to the subject, or contacting said biological sample witha compound of formula I or formula I′ or a composition comprising saidcompound. The term “biological sample,” as used herein, includes,without limitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of Na_(V)1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumchannels in biological and pathological phenomena; and the comparativeevaluation of new sodium channel inhibitors.

SCHEMES AND EXAMPLES

The compounds of the invention may be prepared readily using thefollowing methods. Illustrated below in Scheme 1 through Scheme 3 aregeneral methods for preparing the compounds of the present invention.

EXAMPLES

General methods. ¹H NMR (400 MHz) spectra were obtained as solutions inan appropriate deuterated solvent such as dimethyl sulfoxide-d₆ (DMSO).Mass spectra (MS) were obtained using an Applied Biosystems API EX LC/MSsystem. Compound purity and retention times were determined by reversephase HPLC using a Kinetix C18 column (50×2.1 mm, 1.7 m particle) fromPhenomenex (pn: 00B-4475-AN)), and a dual gradient run from 1-99% mobilephase B over 3 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phaseB=CH₃CN (0.05% CF₃CO₂H). Flow rate=2 mL/min, injection volume=3 μL, andcolumn temperature=50° C. Silica gel chromatography was performed usingsilica gel-60 with a particle size of 230-400 mesh. Pyridine,dichloromethane (CH₂Cl₂), tetrahydrofuran (THF), dimethylformamide(DMF), acetonitrile (ACN), methanol (MeOH), and 1,4-dioxane were fromBaker or Aldrich and in some cases the reagents were Aldrich Sure-Sealbottles kept under dry nitrogen. All reactions were stirred magneticallyunless otherwise noted.

Example 1 Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g,110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to amixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture wasallowed to warm to room temperature and was stirred at that temperatureovernight. The mixture was poured into 1N HCl (200 mL) anddichloromethane (200 mL). The layers were separated and the organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The product was slurried in hexane, the hexane wasdecanted and the product was dried under reduced pressure to yield2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g,74%) as a cream solid. ESI-MS m/z calc. 314.07, found 315.3 (M+1)⁺;Retention time: 1.49 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.1Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.

To 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (1.00g, 3.18 mmol) in acetic acid (6.0 mL) was added HBr (33% in acetic acid)(3.9 mL of 33% w/v, 15.91 mmol) and the mixture stirred at 100° C. for 6hours. Additional HBr (2 mL, 33% in acetic acid) was added and themixture was stirred at room temperature overnight. The mixture was thenheated at 100° C. for 2 hours before it was cooled to room temperature.The mixture was partitioned between ethyl acetate and water. The layerswere separated and the aqueous layer was extracted with ethyl acetate(3×). The combined organics were washed with water and brine (2×), driedover sodium sulfate, filtered and concentrated under reduced pressure.The solid was slurried in methyl-tert-butyl ether and filtered to give2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (731 mg,76%). ESI-MS m/z calc. 301.05, found 301.3 (M+1)⁺; Retention time: 1.35minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.70(s, 1H), 7.96-7.85 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.35 (d, J=7.2 Hz,1H), 6.81 (d, J=1.9 Hz, 1H), 6.41 (dd, J=7.2, 2.1 Hz, 1H) ppm.

Example 2 Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide

A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (25 g, 110.3mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed towarm to room temperature and was stirred at that temperature overnight.The mixture was poured into 1N HCl (200 mL) and dichloromethane (200mL). The layers were separated and the organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure to give2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (33.6 g,97.00%) as an off-white solid. ESI-MS m/z calc. 314.07, found 315.2(M+1)+; Retention time: 1.44 minutes (3 minutes run). ¹H NMR (400 MHz,DMSO-d6) δ 10.94 (s, 1H), 8.12-8.07 (m, 2H), 8.07-7.98 (m, 1H), 7.65 (t,J=9.2 Hz, 1H), 7.24-7.19 (m, 2H), 3.85 (s, 3H) ppm.

To 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (3.54g, 11.27 mmol) in acetonitrile (118.0 mL) was added TMSI (4.0 mL, 28.18mmol). The reaction was stirred at 50° C. overnight. The acetonitrilewas evaporated and the crude re-dissolved in ethyl acetate. The organicswere washed with water, dried over sodium sulfate, filtered andconcentrated. Purification by silica gel chromatography using a gradientof ethyl acetate in hexanes (0-100%) and then methanol indichloromethane (0-20%) gave2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide (3 g,89%), as a brown solid. ESI-MS m/z calc. 300.05, found 301.3 (M+1)⁺;Retention time: 1.34 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 10.85 (s, 1H), 8.10 (dd, J=6.0, 2.2 Hz, 1H), 8.03 (m, 1H), 7.65 (t,J=9.2 Hz, 1H), 7.49 (d, J=7.1 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.57 (dd,J=7.2, 2.1 Hz, 1H), 5.07 (s, 2H) ppm.

Example 3 Preparation of4-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 4-chloro-2-fluoro-benzoic acid (7.0 g, 40.10 mmol), HATU(15.25 g, 40.10 mmol), 2-methoxypyridin-4-amine (4.98 g, 40.10 mmol) andEt₃N (22.4 mL, 160.4 mmol) in dichloromethane (63.0 mL) was stirred atroom temperature overnight. The crude mixture was purified by columnchromatography eluting with a gradient of ethyl acetate in hexanes(0-50%) to yield 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide(4.35 g, 39%), as a white solid. ESI-MS m/z calc. 280.04, found 281.3(M+1)⁺; Retention time: 1.31 minutes (3 minutes run). ¹H NMR (400 MHz,DMSO-d6) δ 10.80 (s, 1H), 8.09 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.66(dd, J=10.1, 1.9 Hz, 1H), 7.46 (dd, J=8.3, 1.9 Hz, 1H), 7.21 (m, 2H),3.84 (s, 3H) ppm.

To 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 15.50mmol) in acetonitrile (145.0 mL) was added TMSI (8.8 mL, 62.0 mmol). Thereaction was stirred at 50° C. overnight. The acetonitrile wasevaporated and the crude solid was triturated with ethyl acetate. Thesolid was isolated by filtration and washed with ethyl acetate to give4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (3.8 g, 92%).ESI-MS m/z calc. 266.02, found 267.1 (M+1)+; Retention time: 1.23minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.73(t, J=8.0 Hz, 1H), 7.68 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (d, J=7.1 Hz,1H), 7.47 (dd, J=8.3, 2.0 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 6.71 (dd,J=7.1, 2.1 Hz, 1H) ppm.

Example 4 Preparation of5-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 5-chloro-2-fluoro-benzoic acid (5.0 g, 28.64 mmol), HATU(10.89 g, 28.64 mmol), 2-methoxypyridin-4-amine (3.6 g, 28.64 mmol) andEt₃N (15.98 mL, 114.60 mmol) in dichloromethane (45.0 mL) was stirred atroom temperature overnight. The crude mixture was purified by columnchromatography eluting with a gradient of ethyl acetate in hexanes(0-50%) to yield 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8g, 47%) as a white solid. ESI-MS m/z calc. 280.04, found 281.3 (M+1)⁺;Retention time: 1.31 minutes (3 minutes run).

To 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 13.50mmol) in acetonitrile (126.3 mL) was added TMSI (7.7 mL, 54.00 mmol).The reaction was stirred at 50° C. overnight. The acetonitrile wasevaporated and the crude re-dissolved in ethyl acetate. The organicswere washed with water, dried over sodium sulfate, filtered andconcentrated. Purification by silica gel chromatography using a gradientof ethyl acetate in hexanes (0-100%) and then methanol indichloromethane (0-20%) yielded5-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (950 mg, 26%) as awhite solid. ESI-MS m/z calc. 266.03, found 267.1 (M+1)⁺; Retentiontime: 1.24 minutes (3 minutes run).

Example 5 Preparation of5-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 4-cyano-2-fluoro-benzoic acid (6.7 g, 40.58 mmol), HATU(15.4 g, 40.58 mmol), 2-methoxypyridin-4-amine (5.0 g, 40.58 mmol) andEt₃N (22.62 mL, 162.3 mmol) in dichloromethane (60.3 mL) was stirred atroom temperature overnight. The crude mixture was purified by columnchromatography using a gradient of ethyl acetate in hexanes (0-50%) toyield 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 66%) asa white solid. ESI-MS m/z calc. 271.07, found 272.1 (M+1)⁺; Retentiontime: 1.17 minutes (3 minutes run).

To 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 26.99 mmol)in acetonitrile (244.0 mL) was added TMSI (9.99 mL, 70.17 mmol). Thereaction was stirred at 50° C. overnight. The acetonitrile wasevaporated and the crude solid was triturated with ethyl acetate. Thesolid was isolated by filtration and washed with ethyl acetate to give4-cyano-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide as a tan solid.ESI-MS m/z calc. 257.06, found 258.1 (M+1)⁺; Retention time: 1.08minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.11(t, J=11.4 Hz, 1H), 7.88 (m, 2H), 7.53 (d, J=7.1 Hz, 1H), 7.01 (d, J=2.0Hz, 1H), 6.60 (dd, J=7.2, 2.1 Hz, 1H) ppm.

Example 6 Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide

A solution of 2-fluoro-5-(trifluoromethoxy)benzoic acid (5.3 g, 23.47mmol), HATU (8.92 g, 23.47 mmol), 2-methoxypyridin-4-amine (2.9 g, 23.47mmol) and Et₃N (13.09 mL, 93.88 mmol) in dichloromethane (47.4 mL) wasstirred at room temperature overnight. The crude mixture was purified bycolumn chromatography eluting with a gradient of ethyl acetate inhexanes (0-50%) to yield2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethoxy)benzamide (5.03 g,65%) as a white solid. ESI-MS m/z calc. 330.06, found 331.1 (M+1)⁺;Retention time: 1.48 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 10.90 (s, 1H), 8.10 (m, 1H), 7.73 (dd, J=5.1, 3.2 Hz, 1H), 7.66 (m,1H), 7.55 (t, J=9.2 Hz, 1H), 7.21 (dd, J=3.7, 1.8 Hz, 2H), 3.84 (s, 3H)ppm.

To 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethoxy)benzamide (5.0g, 15.23 mmol) in acetonitrile (167.6 mL) was added TMSI (5.6 mL, 39.60mmol). The reaction was stirred at 50° C. overnight. The acetonitrilewas evaporated and the crude re-dissolved in ethyl acetate. The organicswere washed with water, dried over sodium sulfate, filtered andconcentrated. Purification by silica gel chromatography a gradient ofethyl acetate in hexanes (0-100%) followed by methanol indichloromethane (0-20%) yielded2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethoxy)benzamide (3 g,62%), as a grey solid. ESI-MS m/z calc. 316.05, found 317.1 (M+1)⁺;Retention time: 1.39 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 10.80 (s, 1H), 7.73 (m, 1H), 7.67 (dd, J=8.7, 3.7 Hz, 1H), 7.55 (t,J=9.1 Hz, 1H), 7.48 (d, J=7.1 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.55 (dd,J=7.2, 2.1 Hz, 1H) ppm.

Example 7 Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide

A solution of 4-bromo-2-fluoro-benzoyl chloride (2 g, 8.42 mmol) indichloromethane (10.0 mL) was added drop-wise to a mixture of2-methoxypyridin-4-amine (1.0 g, 8.42 mmol), pyridine (2.0 mL, 25.27mmol) and dichloromethane (40.0 mL) at 0° C. The mixture was allowed towarm to room temperature and was stirred at that temperature overnight.The mixture was poured into 1N HCl (200 mL) and dichloromethane (200mL). The layers were separated and the organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure to give4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as anoff-white solid. ESI-MS m/z calc. 323.99, found 325.1 (M+1)⁺; Retentiontime: 1.37 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 10.80(s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m,1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H), 3.84 (s, 3H) ppm.

To a stirred solution of4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol)and copper (1.6 g, 24.61 mmol) in DMSO (15 mL), in a bomb,1,1,1,2,2-pentafluoro-2-iodo-ethane (4.1 g, 16.47 mmol) was bubbledthrough. The vessel was sealed and heated at 120° C. for 16 hours. Thereaction mixture was diluted with water and filtered through a plug ofsilica and then extracted with ethyl acetate (4×). The organicscombined, washed with brine, dried over Na₂SO₄, filtered and evaporatedto dryness to yield a crude mixture that was purified by columnchromatography using a gradient of ethyl acetate in hexanes (0-40%) togive2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(200 mg, 22%) as an off white solid. ESI-MS m/z calc. 364.06, found365.3 (M+1)⁺; Retention time: 1.39 minutes (3 minutes run). ¹H NMR (400MHz, DMSO-d6) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.95 (dd, J=7.4Hz, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.23-7.19 (m,2H), 3.85 (s, 3H) ppm.

2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(200 mg, 0.55 mmol) in HBr in acetic acid (1.3 mL of 33% w/v, 5.49 mmol)was stirred at 100° C. for 2 hours, at this time 1 ml of HBr in aceticacid (33% w/v) was added and the mixture was stirred at 100° C. for 4hours, then cooled to room temperature. The reaction mixture was dilutedwith water and a precipitate formed. The precipitate was filtered off,washed with water (2×), cold methyl-tert-butyl ether and dried undervacuum to give2-fluoro-N-(2-oxo-H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(138 mg, 72%) as a light grey solid. ESI-MS m/z calc. 350.05, found351.3 (M+1)+; Retention time: 1.3 minutes (3 minutes run).

Example 8 Preparation of2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 2,5-difluorobenzoyl chloride (2.0 mL, 16.14 mmol) anddichloromethane (14.25 mL) was added drop-wise to a mixture of2-methoxypyridin-4-amine (2.0 g, 16.14 mmol), pyridine (3.9 mL, 48.42mmol) and dichloromethane (57.0 mL) at 0° C. The mixture was allowed towarm to room temperature and was stirred at that temperature overnight.The mixture was poured into 1N HCl and dichloromethane. The layers wereseparated and the organic layer was dried over sodium sulfate, filteredand concentrated under reduced pressure to give a tan solid. The solidwas slurried in hexanes (150 mL) and was filtered to give2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.61 g, 61%) as a tansolid. ESI-MS m/z calc. 264.07, found 265.3 (M+1)⁺; Retention time: 1.22minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H),8.12-8.05 (m, 1H), 7.58 (ddd, J=8.3, 5.4, 2.9 Hz, 1H), 7.52-7.41 (m,2H), 7.25-7.19 (m, 2H), 3.84 (s, 3H) ppm.

To 2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.60 g, 9.84 mmol) inacetic acid (15.60 mL) was added HBr 33% in acetic acid (12.1 mL of 33%w/v, 49.20 mmol) and the mixture was stirred at 90° C. for 5 h.Additional HBr (10 mL, 33% in acetic acid) was added and the mixture wasstirred at 90° C. overnight. The mixture was cooled to room temperatureand was poured into water (200 mL). The mixture was stirred and thesolid was collected by filtration. The solid was washed with water (2×50mL). The solid was slurried in hexanes (2×50 mL) and filtered to give2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (2.30 g, 9.19 mmol,93%). ESI-MS m/z calc. 250.05, found 251.3 (M+1)⁺; Retention time: 1.16minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H),10.59 (s, 1H), 7.56 (ddd, J=8.2, 5.4, 3.0 Hz, 1H), 7.46 (pd, J=9.1, 4.4Hz, 2H), 7.33 (d, J=7.2 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.42 (dd,J=7.2, 2.1 Hz, 1H) ppm.

Example 9 Preparation of4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol),4,5-dichloro-2-fluoro-benzoic acid (285.1 mg, 1.36 mmol), HATU (622.4mg, 1.64 mmol) and n-methylmorpholine (299.9 μL, 2.73 mmol) in DMF (3mL) was stirred at room temperature for 16 hours. The reaction mixturewas poured into water and extracted with ethyl acetate (3×). Theorganics were combined, washed with water (3×), brine and dried overNa₂SO₄, filtered through a short plug of silica and evaporated todryness. The material was taken up in HBr (in acetic acid) (6.689 mL of33% w/v, 27.28 mmol) and stirred at 95° C. for 16 h. The solution wascooled to room temperature, filtered and solid product washed with water(2×) and then ether (2×) and dried under vacuum to give4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (250 mg, 61%)as an off white solid. ESI-MS m/z calc. 299.99, found 301.3 (M+1)⁺;Retention time: 1.16 minutes (3 minutes run).

Example 10 Preparation of4-chloro-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 4-chloro-2,5-difluoro-benzoyl chloride (5 g, 23.70 mmol)in dichloromethane (25 mL) was added dropwise to a mixture of2-methoxypyridin-4-amine (2.94 g, 23.70 mmol), pyridine (5.75 mL, 71.10mmol) and dichloromethane (100.0 mL) at 0° C. The mixture was allowed towarm to room temperature and was stirred at that temperature for 43hours. The mixture was poured into 1N HCl (50 mL). The mixture wasfiltered using dichloromethane and the solid was isolated. The solid wasdried under vacuum to yield4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (6.2 g, 88%) as apink solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.16-8.05 (m,1H), 7.97-7.75 (m, 2H), 7.29-7.15 (m, 2H), 3.85 (s, 3H) ppm. ESI-MS m/zcalc. 298.03, found 299.3 (M+1)+; Retention time: 1.43 minutes (3minutes run).

To 4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (3 g, 10.04mmol) in HOAc (15.9 mL) was added HBr 33% in HOAc (12.31 mL of 33% w/v,50.20 mmol) and the mixture was stirred at 90° C. for 5 h. AdditionalHBr (10 mL, 33% in HOAc) was added and the mixture was stirred at 90° C.overnight. The mixture was cooled to room temperature and was pouredinto water (100 mL). The mixture was stirred and the solid was collectedby filtration. The solid was washed with water (2×50 mL). The solid wasslurried in hexanes (2×50 mL) and filtered to give4-chloro-2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (969.7 mg, 34%)as a cream colored solid. ESI-MS m/z calc. 284.02, found 285.3 (M+1)+;Retention time: 1.36 minutes (3 min run).

Example 11 Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide

2-Methoxypyridin-4-amine (632.1 mg, 5.09 mmol) and DIEA (1.8 mL, 10.18mmol) were dissolved in DMF (15 mL) and treated dropwise with a solutionof 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1500 mg, 5.09mmol) in DMF (2 mL). After 2 hours, the reaction was diluted with ethylacetate, washed with 50% saturated sodium bicarbonate solution (2×20mL), water, and brine. The solution was dried over anhydrous Na₂SO₄,filtered, and dried down to a purple residue. Silica gel chromatographyusing a gradient of ethyl acetate/hexane (10-99%) provided2-fluoro-N-(2-methoxypyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide(1.2 g, 67%) as a beige solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.29 (s,1H), 8.42 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.13 (dd, J=5.4, 0.9 Hz, 1H),7.14-7.10 (m, 2H), 3.85 (s, 3H) ppm. ESI-MS m/z calc. 382.05, found383.1 (M+1)+; Retention time: 1.48 minutes (3 minutes run).

To a mixture of sodium iodide (2.54 g, 16.95 mmol) in acetonitrile (75mL) under nitrogen was added TMSCl (2.15 mL, 16.95 mmol) and the mixturewas stirred at 25° C. for 30 min. Thereafter, anhydrous acetonitrile(130.0 ml) was added to this solution followed by2-fluoro-N-(2-methoxy-4-pyridyl)-4,6-bis(trifluoromethyl)benzamide (1.2g, 3.14 mmol). The resulting reaction mixture was heated with stirringat 80° C. for 5 h and at 60° C. for 12 hours. The reaction was cooled,diluted with water, and extracted with ethyl acetate. The organic layerwas dried over Na₂SO₄, filtered and concentrated to a dark yellow-orangesolid. The solid was triturated with ethyl acetate/hexanes several timesto remove dark red color, then with dichloromethane to remove yellowcolor, then finally with hexanes. The resulting solid was dried undervacuum to provide2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide(960 mg, 83%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.41(s, 1H), 11.03 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H),7.37 (d, J=7.1 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 6.31 (dd, J=7.2, 2.1 Hz,1H) ppm. ESI-MS m/z calc. 368.04, found 369.1 (M+1)+; Retention time:1.28 minutes (3 minutes run).

Example 12 Preparation ofN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide(79)

Cs₂CO₃ (651.6 mg, 2 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(60.0 mg, 0.2 mmol) and 4-(trifluoromethoxy)phenol (259.1 μL, 2 mmol) inDMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (10-99%) and HCl as a modifier toyieldN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide(79) (25.7 mg, 28%). ESI-MS m/z calc. 458.07, found 459.5 (M+1)⁺;Retention time: 1.80 minutes (3 minutes run)

Example 13 Preparation of2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(159)

To a solution of2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (211.2mg, 0.70 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (100 mg, 0.70 mmol)in N-methyl pyrrolidinone (3 mL) was added cesium carbonate (687.8 mg,2.1 mmol) and the mixture was heated at 100° C. for 2 hours. Thereaction was cooled to 25° C., filtered and purified by reverse phaseHPLC using a gradient of acetonitrile/water (10 to 99%) and HCl as amodifier to yield2-[(5-fluoro-2-hydroxy-phenyl)methoxy]-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide(159) (10.5 mg, 3%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.52(s, 1H), 10.49 (s, 1H), 10.04 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.78 (d,J=7.4 Hz, 1H), 7.33-7.23 (m, 2H), 7.05-6.91 (m, 2H), 6.91-6.79 (m, 2H),6.61 (dd, J=7.4, 2.4 Hz, 1H), 4.96 (s, 2H) ppm. ESI-MS m/z calc. 422.09,found 423.3 (M+1)+; Retention time: 1.83 minutes (3 minutes).

Example 14 Preparation of2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(10)

A mixture of2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)-benzamide (13.6g, 45.30 mmol), 4-fluoro-2-methyl-phenol (17.1 g, 135.9 mmol), Cs₂CO₃(44.28 g, 135.9 mmol) and DMF (340.0 mL) was heated at 100° C. for 1.5hours. The mixture was cooled to room temperature and was poured intowater (500 mL). The mixture was stirred vigorously for 30 min before itwas filtered. The solid was washed with water (250 mL) and was slurriedwith methyl tert-butyl ether (200 mL). The mixture was filtered and thesolid was slurried with hexanes (2×400 mL) and the filtrate was driedunder vacuum to give2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide(10) (13.1 g, 70%) as a solid. ESI-MS m/z calc. 406.09, found 407.5(M+1)⁺; Retention time: 1.73 minutes (3 minutes run). ¹H NMR (400 MHz,DMSO-d6) δ 11.28 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60(d, J=7.1 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.14-7.06(m, 2H), 7.00-6.95 (m, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.1Hz, 1H), 2.16 (s, 3H) ppm.

Example 15 Preparation of2-(4-fluoro-2-(hydroxymethyl)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(157)

2-Fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (625.3mg, 2.08 mmol), potassium carbonate (287.9 mg, 2.08 mmol) and4-fluoro-2-(hydroxymethyl)phenol (296 mg, 2.08 mmol) were added to1-methylpyrrolidin-2-one (3.0 mL) and the reaction was stirred at 80° C.for 10 minutes. The reaction was filtered and the compound was purifiedby reverse phase preparative chromatography utilizing a gradient of10-99% acetonitrile in water containing HCl as a modifier to yield2-[4-fluoro-2-(hydroxymethyl)phenoxy]-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide(157) (10.3 mg, 1%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.44(s, 1H), 10.66 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H),7.41-7.27 (m, 2H), 7.24-7.12 (m, 1H), 7.12-7.07 (m, 1H), 7.04 (s, 1H),6.80 (d, J=2.1 Hz, 1H), 6.43 (dd, J=7.3, 2.2 Hz, 1H), 4.47 (s, 2H) ppm.ESI-MS m/z calc. 422.09, found 423.2 (M+1)+; Retention time: 1.32minutes (3 minutes run).

Example 16 Preparation of2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(81)

Cs₂CO₃ (651.6 mg, 2.0 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(60.0 mg, 0.2 mmol) and 3-fluoro-4-methoxyphenol (284.3 mg, 2.0 mmol) inDMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (10-99%) and HCl as a modifier toyield2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(81) (45.6 mg, 54%). ESI-MS m/z calc. 422.09, found 423.3 (M+1)⁺;Retention time: 1.65 minutes (3 minutes run).

Following a similar procedure as described above for compound 81, thefollowing compounds were prepared from2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamidein each case and using the alcohols described below.

Cmpd No. Product Alcohol 144 N-(2-oxo-1,2-dihydropyridin-4-yl)-4-6-(trifluoromethyl)pyridin-(trifluoromethyl)-2-((6-(trifluoromethyl)pyridin-3- 3-olyl)oxy)benzamide 116 2-(isopentyloxy)-N-(2-oxo-1,2-dihydropyridin-4-isopentanol yl)-4-(trifluoromethyl)benzamide 52-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin- 4-fluorophenol4-yl)-4-(trifluoromethyl)benzamide 72-(2,4-difluorophenoxy)-N-(2-oxo-1,2- 2,4-difluorophenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 1172-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-4- isobutanol(trifluoromethyl)benzamide 1462-((6-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2- 6-methyl-3-pyridinoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 1182-[(1R,2R,4S)-norbornan-2-yl]oxy-N-(2-oxo-1H- (1R,2R,4S)-norbornan-2-olpyridin-4-yl)-4-(trifluoromethyl)benzamide 1472-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2- 2-methyl-3-pyridinoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 1192-((1-methylcyclopropyl)methoxy)-N-(2-oxo-1,2- 1-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamidemethylcyclopropyl)methanol 120 2-(cyclopentylmethoxy)-N-(2-oxo-1,2-cyclopentylmethanol dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide121 N-(2-oxo-1,2-dihydropyridin-4-yl)-2- tetrahydrofuran-3-((tetrahydrofuran-3-yl)methoxy)-4- ylmethanol (trifluoromethyl)benzamide122 2-cyclobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)- cyclobutanol4-(trifluoromethyl)benzamide 123N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4- 4,4,4-trifluorobutanoltrifluorobutoxy)-4-(trifluoromethyl)benzamide 1242-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo- 2,2-1,2-dihydropyridin-4-yl)-4- dimethylcyclopropyl)(trifluoromethyl)benzamide methanol 1252-((1R,5S)-bicyclo[3.1.0]hexan-3-yloxy)-N-(2-oxo- (1R,5S)-3-1,2-dihydropyridin-4-yl)-4- bicyclo[3.1.0]hexanol(trifluoromethyl)benzamide 1262-((2,2-difluorocyclopropyl)methoxy)-N-(2-oxo- 2,2-1,2-dihydropyridin-4-yl)-4- difluorocyclopropyl)(trifluoromethyl)benzamide methanol 82-(4-(2-methoxyethoxy)phenoxy)-N-(2-oxo-1,2- 4-(2-methoxyethoxy)phenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 1272-(bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-1,2- norbornan-2-oldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 9N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-4- phenol(trifluoromethyl)benzamide 11N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)- 2-methylphenol4-(trifluoromethyl)benzamide 1282-(cyclohexyloxy)-N-(2-oxo-1,2-dihydropyridin-4- cyclohexanolyl)-4-(trifluoromethyl)benzamide 12N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)- 4-methylphenol4-(trifluoromethyl)benzamide 772-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2- 2-chloro-4-fluoro-phenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 782-(4-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin- 4-chlorophenol4-yl)-4-(trifluoromethyl)benzamide 80N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2- 2-(trifluoromethoxy)phenol(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide 822-(4-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2- 4-(difluoromethoxy)phenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 832-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2- 2-(difluoromethoxy)phenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 842-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2- 2-fluoro-4-methoxy-phenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 872-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- 3 -fluoro-2-methoxy-phenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 1102-(2-chloro-3-fluoro-4-methoxyphenoxy)-N-(2-oxo- 2-chloro-3-fluoro-4-1,2-dihydropyridin-4-yl)-4- methoxy-phenol (trifluoromethyl)benzamide158 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- 4-fluoro-2-methoxyphenoldihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

Example 17 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide(30)

Cs₂CO₃ (651.6 mg, 2.0 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide(60.0 mg, 0.2 mmol) and 4-fluoro-3-methoxyphenol (228 μl, 2.0 mmol) inDMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (10-99%) and HCl as a modifier toyield2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide(30) (67.9 mg, 80%). ESI-MS m/z calc. 422.09, found 423.2 (M+1)⁺;Retention time: 1.56 minutes (3 minutes run).

Following a similar procedure as described above for compound 30, thefollowing compounds were prepared from2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamideand the following alcohols.

Cmpd No. Product Alcohol 72 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-4-(trifluoromethoxy)phenol (trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 31 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-4-fluoro-2-methyl-phenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 632-(4-methoxy-2-methylphenoxy)-N-(2-oxo-1,2- 4-methoxy-2-methyl-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 502-(4-chloro-2-methylphenoxy)-N-(2-oxo-1,2- 4-chloro-2-methyl-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 442-(4-ethoxyphenoxy)-N-(2-oxo-1,2- 4-ethoxyphenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 492-(2-chloro-4-methoxyphenoxy)-N-(2-oxo-1,2- 2-chloro-4-methoxy-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 90N-(2-oxo-1,2-dihydropyridin-4-yl)-5- 2,3,4-trifluorophenol(trifluoromethyl)-2-(2,3,4- trifluorophenoxy)benzamide 292-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2- 2-chloro-4-fluoro-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 542-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- 3-fluoro-2-methoxy-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 592-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2- 3-fluoro-4-methoxy-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 62N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2- 2-propoxyphenolpropoxyphenoxy)-5-(trifluoromethyl)benzamide 732-(4-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2- 4-(difluoromethoxy)phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 28N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o- 2-methylphenoltolyloxy)-5-(trifluoromethyl)benzamide 53N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4- 4-propoxyphenolpropoxyphenoxy)-5-(trifluoromethyl)benzamide 75N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2- 2-(trifluoromethoxy)phenol(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamide 22-(4-fluorophenoxy)-N-(2-oxo-1,2- 4-fluorophenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 762-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2- 2-(difluoromethoxy)phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 582-(4-chlorophenoxy)-N-(2-oxo-1,2- 4-chlorophenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 24 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-2,4-difluorophenol dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 462-(2-ethoxyphenoxy)-N-(2-oxo-1,2- 2-ethoxyphenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 45 2-(4-methoxyphenoxy)-N-(2-oxo-1,2-4-methoxyphenoxy dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 562-(5 -fluoro-2-methylphenoxy)-N-(2-oxo-1,2- 5-fluoro-2-methyl-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 552-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2- 2-fluoro-4-methoxy-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 512-(4-chloro-2-fluorophenoxy)-N-(2-oxo-1,2- 4-chloro-2-fluoro-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 522-(5-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- 5-fluoro-2-methoxy-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 652-(2-chlorophenoxy)-N-(2-oxo-1,2- 2-chlorophenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 64 2-(2-isopropoxyphenoxy)-N-(2-oxo-1,2-2-isopropoxyphenol dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 612-(4-fluoro-2-methylphenoxy)-N-(6-methyl-2- 4-fluoro-2-methyl-phenoloxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 472-(2-methoxy-4-methylphenoxy)-N-(2-oxo-1,2- 2-methoxy-4-methyl-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 922-(2,3-difluoro-4-methylphenoxy)-N-(2-oxo- 1,2-2,3-difluoro-4-methyl-phenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 32N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-5- phenol(trifluoromethyl)benzamide 132 N-(2-oxo-1,2-dihydropyridin-4-yl)-5-3,3,3-trifluoropropanol (trifluoromethyl)-2-(3,3,3-trifluoropropoxy)benzamide 27 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-4-methylphenol tolyloxy)-5-(trifluoromethyl)benzamide 91-(2-oxo-1,2-dihydropyridin-4-yl)-5- 2,3,5-trimethylphenol(trifluoromethyl)-2-(2,3,5- trimethylphenoxy)benzamide 252-(4-cyanophenoxy)-N-(2-oxo-1,2- 4-cyanophenol dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 93 N-(2-oxo-1,2-dihydropyridin-4-yl)-5-2,4,5-trimethylphenol (trifluoromethyl)-2-(2,4,5-trimethylphenoxy)benzamide 131 2-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- isobutanol (trifluoromethyl)benzamide 1352-[[(1R,5S)-3-bicyclo[3.1.0]hexanyl]oxy]-N-(2- (1R,5S)-3-oxo-1H-pyridin-4-yl)-5- bicyclo[3.1.0]hexanol (trifluoromethyl)benzamide48 2-(2-fluoro-6-methoxyphenoxy)-N-(2-oxo-1,2- 2-fluoro-6-methoxy-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 862-(4-fluoro-2-methylphenoxy)-N-(5-methyl-2- 4-fluoro-2-methyl-phenoloxo-1,2-dihydropyridin-4-yl)-4- (trifluoromethyl)benzamide 1302-(cyclopentylmethoxy)-N-(2-oxo-1,2- cyclopentylmethanoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 74N-(2-oxo-1,2-dihydropyridin-4-yl)-5- 4-(trifluoromethyl)phenol(trifluoromethyl)-2-(4- (trifluoromethyl)phenoxy)benzamide 133N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4- 4,4,4-trifluorobutanoltrifluorobutoxy)-5-(trifluoromethyl)benzamide 1502-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2- 2-methyl-3-pyridinoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 572-(3-fluoro-5-methoxyphenoxy)-N-(2-oxo-1,2- 3-fluoro-5-methoxy-phenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 262-(2,6-difluorophenoxy)-N-(2-oxo-1,2- 2,6-difluorophenoldihydropyridin-4-yl)-5- (trifluoromethyl)benzamide 1342-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo- 2,2-1,2-dihydropyridin-4-yl)-5- dimethylcyclopropyl)methanol(trifluoromethyl)benzamide

Example 18 Preparation of5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(70)

Cs₂CO₃ (879.9 mg, 2.7 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-chlorobenzamide (72.0 mg,0.27 mmol) and 4-fluoro-3-methoxyphenol (307.7 μl, 2.7 mmol) in DMF (1mL) and the reaction was stirred at 100° C. for 1 hour. The reaction wasfiltered and purified by reverse phase HPLC using a gradient ofacetonitrile in water (10-99%) and HCl as a modifier to yield5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(70) (31.8 mg, 30%). ESI-MS m/z calc. 388.06, found 389.10 (M+1)⁺;Retention time: 1.52 minutes (3 minutes run).

Following a similar procedure as described above for compound 70, thefollowing compounds were prepared from5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideand the following alcohols.

Cmpd No. Product Alcohol 68 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-fluoro-2-methyl- N-(2-oxo-1,2-dihydropyridin-4-yl) phenol benzamide 665-chloro-2-(2-chloro-4-fluorophenoxy)- 2-chloro-4-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl) phenol benzamide 675-chloro-2-(4-fluorophenoxy)-N-(2-oxo- 4-fluorophenol1,2-dihydropyridin-4-yl)benzamide 715-chloro-2-(3-fluoro-4-methoxyphenoxy)- 3-fluoro-4-methoxy-N-(2-oxo-1,2-dihydropyridin-4-yl) phenol benzamide

Example 19 Preparation of4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(16)

Cs₂CO₃ (651.6 mg, 2.0 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-chlorobenzamide (53.3 mg,0.20 mmol) and 4-fluoro-3-methoxyphenol (284.3 mg, 2.0 mmol) in DMF (1mL) and the reaction was stirred at 100° C. for 1 hour. The reaction wasfiltered and purified by reverse phase HPLC using a gradient ofacetonitrile in water (10-99%) and HCl as a modifier to yield4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(16) (22.1 mg, 28%). ESI-MS m/z calc. 388.06, found 389.15 (M+1)⁺;Retention time: 1.53 minutes (3 minutes run).

Following a similar procedure as described above for compound 16, thefollowing compounds were prepared from4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideand the following alcohols.

Cmpd No. Product Alcohol 20 4-chloro-2-(4-fluoro-2-methylphenoxy)-4-fluoro-2-methyl- N-(2-oxo-1,2-dihydropyridin-4-yl) phenol benzamide 144-chloro-2-(2-chloro-4-fluorophenoxy)- 2-chloro-4-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl) phenol benzamide 154-chloro-2-(4-fluorophenoxy)-N-(2-oxo- 4-fluorophenol1,2-dihydropyridin-4-yl)benzamide 134-chloro-2-(2,4-difluorophenoxy)-N-(2- 2,4-difluorophenoloxo-1,2-dihydropyridin-4-yl)benzamide 1294-chloro-N-(2-oxo-1,2-dihydropyridin-4- 4,4,4-trifluorobutanolyl)-2-(4,4,4-trifluorobutoxy)benzamide 174-chloro-2-(2-fluoro-6-methylphenoxy)- 2-fluoro-6-methyl-N-(2-oxo-1,2-dihydropyridin-4-yl) phenol benzamide 1434-chloro-N-(2-oxo-1,2-dihydropyridin-4- 6-(trifluoromethyl)-3-yl)-2-((6-(trifluoromethyl)pyridin-3- pyridinol yl)oxy)benzamide 194-chloro-2-(2,6-difluorophenoxy)-N-(2- 2,6-difluorophenoloxo-1H-pyridin-4-yl)benzamide 18 4-chloro-2-(2-chloro-6-fluorophenoxy)-2-chloro-6-fluoro- N-(2-oxo-1,2-dihydropyridin-4-yl) phenol benzamide

Example 20 Preparation of4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(114)

Cs₂CO₃ (97.7 mg, 0.3 mmol) was added to a solution of4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (30.1mg, 0.1 mmol) and 4-fluoro-3-methoxyphenol (42.6 mg, 0.3 mmol) in NMP(0.5 mL) and the reaction was stirred at 90° C. for 2 hours. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (1-99%) and HCl as a modifier to yield4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(114) (13.2 mg, 30%). ESI-MS m/z calc. 422.02, found 423.3 (M+1)⁺;Retention time: 1.57 minutes (3 minutes run).

Following a similar procedure as described above for compound 114, thefollowing compounds were prepared from4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide and thefollowing alcohols.

Cmpd No. Product Alcohol 113 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-4-fluorophenol 1,2-dihydropyridin-4-yl)benzamide 1154,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)- 3-fluoro-4-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide methoxy-phenol

Example 21 Preparation of2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide(40)

Cs₂CO₃ (651.6 mg, 2 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide(63.2 mg, 0.2 mmol) and 4-fluoro-3-methylphenol (252.3 mg, 2 mmol) inDMF (1 mL) and the reaction was stirred at 100° C. for 1 hours. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (10-99%) and HCl as a modifier toyield2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide(40) (36.3 mg, 43%). ESI-MS m/z calc. 422.09, found 423.9 (M+1)⁺;Retention time: 1.64 minutes (3 minutes run).

Following a similar procedure as described above for compound 40, thefollowing compounds were prepared from2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamideand the following alcohols.

Cmpd No. Product Alcohol 37 2-(2-chloro-4-fluorophenoxy)-N-2-chloro-4-fluoro-phenol (2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 42 2-(4-fluoro-2-methoxyphenoxy)-N-4-fluoro-2-methoxy-phenol (2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 38 2-(4-fluorophenoxy)-N-(2-oxo-1,2-4-fluorophenol dihydropyridin-4-yl)-5- (trifluoromethoxy)benzamide 332-(2,4-difluorophenoxy)-N-(2-oxo- 2,4-difluorophenol1,2-dihydropyridin-4-yl)-5- (trifluoromethoxy)benzamide 36N-(2-oxo-1,2-dihydropyridin-4-yl)- 2-methylphenol2-(o-tolyloxy)-5-(trifluoromethoxy) benzamide 41N-(2-oxo-1,2-dihydropyridin-4-yl)- phenol p2-henoxy-5-(trifluoromethoxy)benzamide 35 N-(2-oxo-1,2-dihydropyridin-4-yl)- 4-methylphenol2-(p-tolyloxy)-5-(trifluoromethoxy) benzamide 392-(2-fluoro-6-methylphenoxy)-N- 2-fluoro-6-methyl-phenol(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethoxy)benzamide 138N-(2-oxo-1,2-dihydropyridin-4-yl)- 3,3,3-trifluoropropanol5-(trifluoromethoxy)-2-(3,3,3- trifluoropropoxy)benzamide 1362-(cyclopentylmethoxy)-N-(2-oxo- cyclopentylmethanol1,2-dihydropyridin-4-yl)-5- (trifluoromethoxy)benzamide 139N-(2-oxo-1,2-dihydropyridin-4-yl)- 4,4,4-trifluorobutanol(2-4,4,4-trifluorobutoxy)-5- (trifluoromethoxy)benzamide 1512-((2-methylpyridin-3-yl)oxy)-N- 2-methyl-3-pyridinol(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethoxy)benzamide 342-(2,6-difluorophenoxy)-N-(2-oxo- 2,6-difluorophenol1,2-dihydropyridin-4-yl)-5- (trifluoromethoxy)benzamide 1372-(cyclohexyloxy)-N-(2-oxo-1,2- cyclohexanol dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 140 2-((2,2-dimethylcyclopropyl) 2,2-methoxy)-N-(2-oxo-1,2- dimethylcyclopropyl) dihydropyridin-4-yl)-5-methanol (trifluoromethoxy)benzamide

Example 22 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide(111)

Cs₂CO₃ (69.8 mg, 0.21 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide(25 mg, 0.07 mmol) and 4-fluoro-2-methoxyphenol (24.4 μL, 0.2 mmol) inNMP (0.3 mL) and the reaction was stirred at 100° C. for 45 minutes. Thereaction mixture was poured into water:ethyl acetate (9:1). The mixturewas shaken, and the solid was filtered off, washed with ether, thentriturated with ethyl acetate and dried to give the desired product. Themother liquors were filtered and washed with ethyl acetate to give asecond crop of material. Both solids were combined and dried undervacuum to give2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(111) (15.4 mg, 45%) as a white solid. ESI-MS m/z calc. 472.08, found473.3 (M+1)+; Retention time: 1.62 minutes. ¹H NMR (400 MHz, DMSO) δ11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.9 Hz,1H), 7.39-7.27 (m, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 (dd, J=11.3,5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73(s, 3H) ppm.

Following a similar procedure as described above for compound 111, thefollowing compounds were prepared from2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamideand the following alcohols.

Cmpd. No. Product Alcohol 88 2-(4-fluorophenoxy)-N-(2-oxo-1,2-4-fluorophenol dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide 1122-(4-fluoro-2-methylphenoxy)-N- 4-fluoro-2-methyl-phenol(2-oxo-1,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide 892-(3-fluoro-4-methoxyphenoxy)-N- 3-fluoro-4-methoxy-phenol(2-oxo-1,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide

Example 23 Preparation of4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(22)

Cs₂CO₃ (651.4 mg, 2.0 mmol) was added to a solution of4-cyano-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (51.4 mg,0.2 mmol) and 4-fluoro-2-methoxyphenol (244 μL, 2.0 mmol) in DMF (1 mL)and the reaction was stirred at 100° C. for 1 hour. The reaction wasfiltered and purified by reverse phase HPLC using a gradient ofacetonitrile in water (10-99%) and HCl as a modifier to yield4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(22) (26.8 mg, 35%). ESI-MS m/z calc. 379.10, found 380.17 (M+1)+;Retention time: 1.30 minutes (3 minutes run).

Following a similar procedure as described above for compound 22, thefollowing compounds were prepared from2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(perfluoroethyl)benzamideand the following alcohols.

Cmpd No. Product Alcohol 21 4-cyano-2-(4-fluorophenoxy)-N-(2-oxo-4-fluorophenol 1,2-dihydropyridin-4-yl)benzamide 234-cyano-2-(4-fluoro-2-methylphenoxy)-N- 4-fluoro-2-methyl-(2-oxo-1,2-dihydropyridin-4-yl)benzamide phenol

Example 24 Preparation of5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide(101)

Cs₂CO₃ (146.6 mg, 0.45 mmol) was added to a solution of2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (37.5 mg, 0.15mmol) and 4-trifluoro methoxyphenol (80.1 mg, 0.45 mmol) in DMF (0.9 mL)and the reaction was stirred at 100° C. for 8 hours. The reaction wasfiltered and purified by reverse phase HPLC using a gradient ofacetonitrile in water (10-99%) and HCl as a modifier to yield5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide(101) (1.9 mg, 3%). ESI-MS m/z calc. 408.07, found 409.3 (M+1)+;Retention time: 1.68 minutes (3 minutes run).

Following a similar procedure as described above for compound 101, thefollowing compounds were prepared from2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide and thefollowing alcohols.

Cmpd No. Product Alcohol 100 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-propoxyphenol 4-(yl)-2-4-propoxyphenoxy) benzamide 1082-(4-(cyclopropylmethoxy)phenoxy)- 4-(cyclopropylmethoxy)5-fluoro-N-(2-oxo-1,2-dihydropyridin- phenol 4-yl)benzamide 982-(4-ethoxyphenoxy)-5-fluoro-N-(2- 2-(4-ethoxyphenoloxo-1,2-dihydropyridin-4-yl) benzamide 1032-(2-chloro-4-methoxyphenoxy)-5- 2-chloro-4-methoxy-fluoro-N-(2-oxo-1,2-dihydropyridin- phenol 4-yl)benzamide 1075-fluoro-N-(2-oxo-1,2-dihydropyridin- 4-(2,2,2-trifluoroethoxy)(4-yl)-2-4-(2,2,2-trifluoroethoxy) phenol phenoxy)benzamide 962-(4-cyclopropylphenoxy)-5-fluoro- 2-(4-cyclopropylphenol(N-2-oxo-1,2-dihydropyridin-4-yl) benzamide 972-(4-(tert-butoxy)phenoxy)-5-fluoro- 2-(4-tert-butoxyphenolN-(2-oxo-1,2-dihydropyridin-4-yl) benzamide 1045-fluoro-2-(4-methoxyphenoxy)-N- 4-methoxyphenol(2-oxo-1,2-dihydropyridin-4-yl) benzamide 945-fluoro-N-(2-oxo-1,2-dihydropyridin- 2,3,5-trimethylphenol4-yl)-2-(2,3,5-trimethylphenoxy) benzamide 955-fluoro-N-(2-oxo-1,2-dihydropyridin- phenol 4-yl)-2-phenoxybenzamide105 5-fluoro-N-(2-oxo-1,2-dihydropyridin- 2,4,5-trimethylphenol4-yl)-(2-2,4,5-trimethylphenoxy) benzamide 995-fluoro-2-(4-isopropylphenoxy)-N- 4-isopropylphenol(2-oxo-1,2-dihydropyridin-4-yl) benzamide 1025-fluoro-2-(4-(2-methoxyethyl) 4-(2-methoxyethyl) phenoxy)-N-(2-oxo-1,2-phenol dihydropyridin-4-yl)benzamide 1605-fluoro-N-(2-oxo-1,2-dihydropyridin- 4-(4,4,4-trifluorobutoxy)4-yl)-2-(4-(4,4,4-trifluorobutoxy) phenol phenoxy)benzamide

Example 25 Preparation of4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(109)

Cs₂CO₃ (244.4 mg, 0.75 mmol) was added to a solution of4-chloro-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (71.2mg, 0.25 mmol) and 2-chloro-4-fluorophenol (109.9 mg, 0.75 mmol) in DMF(2 mL) and the reaction was stirred at 100° C. for 1 hours. The reactionwas filtered and purified by reverse phase HPLC using a gradient ofacetonitrile in water (10-99%) and HCl as a modifier to yield4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(109) (22.8 mg, 27%). ESI-MS m/z calc. 410.00, found 411.2 (M+1)+;Retention time: 1.76 minutes (3 minutes run).

Example 26 Preparation of2-(4-fluoro-2-methylphenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)benzamide(106)

To a solution of 6-methoxypyridin-3-amine (20.5 mg, 0.16 mmol) indichloromethane (0.5 mL) was added2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl chloride (50mg, 0.15 mmol) followed by di-isopropylethyl amine (26.2 μL, 0.15 mmol)and the reaction mixture was stirred at 25° C. for 16 hours and then thesolvent was evaporated.

The crude material from the amide formation was dissolved in HBr (inAcOH) (250 μL of 33% w/v, 1.02 mmol) and heated at 80° C. for 8 hours.The reaction mixture was diluted with water and extracted with ethylacetate (3×). The organics were combined and evaporated to dryness.Purification by HPLC (1-99% ACN in Water with HCl as a modifier) gave2-(4-fluoro-2-methyl-phenoxy)-N-(6-oxo-1H-pyridin-3-yl)-5-(trifluoromethyl)benzamide (106) (29.97 mg, 45%) as a white solid. ESI-MS m/z calc.406.09, found 407.10 (M+1)+; Retention time: 1.52 minutes (3 minutesrun).

Example 27 Preparation of4-(tert-butyl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide(141)

A solution of4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzoic acid(169.7 mg, 0.5 mmol), HATU (190 mg, 0.5 mmol), 2-methoxypyridin-4-amine(62.1 mg, 0.5 mmol) and tri-ethyl amine (278.8 μL, 2 mmol) indichloromethane (5 mL) was stirred at room temperature over 72 hours.The reaction was purified by silica gel chromatography using gradient ofethyl acetate in hexanes (0-40%) to yield4-(tert-butyl)-N-(2-methoxypyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide(137 mg, 60%). ESI-MS m/z calc. 445.16, found 446.3 (M+1)+; Retentiontime: 1.87 minutes (3 minutes run).

To the4-(tert-butyl)-N-(2-methoxypyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide(137 mg, 0.3 mmol) in acetonitrile (4.9 mL) was added TMSI (93.3 μL,0.66 mmol). The reaction was stirred at 50° C. for 12 hours. Thereactions was cooled to 25° C., filtered and purified by reverse phaseHPLC (10-99% ACN in Water with HCl as a modifier) to yield4-(tert-butyl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide(141) (14.4 mg, 13%). ESI-MS m/z calc. 431.15, found 432.3 (M+1)+;Retention time: 1.78 minutes (3 minutes run).

The following products were prepared using a similar reaction sequenceas described above for compound 141.

Cmpd No. Product 6 2-(4-fluorophenoxy)-N-(6-oxo-1H-pyridin-3-yl)-4-(trifluoromethyl)benzamide 42-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)benzamide 432-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)benzamide 1424-(tert-butyl)-N-(6-oxo-1,6-dihydropyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide 12-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl) benzamide 145N-(6-oxo-1,6-dihydropyridin-3-yl)-4-(trifluoromethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide 32-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl) benzamide

Example 28 Preparation of4-(tert-butyl)-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide(148)

A solution of4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzoic acid(67.9 mg, 0.2 mmol), HATU (66 mg, 0.2 mmol),5-amino-1-methylpyridyl-2-one (24.8 mg, 0.2 mmol) and triethylamine (111μL, 0.8 mmol) in dichloromethane (0.9 mL) was stirred at roomtemperature over 72 hours. The reaction was filtered and purified byreverse phase HPLC using a gradient of acetonitrile in water (10-99%)and HCl as a modifier to yield4-(tert-butyl)-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide(148) (1.2 mg, 1%). ESI-MS m/z calc. 445.16, found 446.3 (M+1)+;Retention time: 1.85 minutes (3 minutes run).

4-tert-Butyl-N-(1-methyl-6-oxo-3-pyridyl)-2-[[6-(trifluoromethyl)-3-pyridyl]oxy]benzamide(149) was prepared using a similar reaction sequence as described abovefor compound 148.

Example 29 Preparation of2-(4-fluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(85)

To2-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide(78.5mg, 0.2 mmol), in DMF (1 ml) was added sodium hydride (4.8 mg, 0.20mmol) and 2-bromoethanol (14.17 μL, 0.20 mmol) and the reaction wasstirred at room temperature for 16 hours. The reaction was reloaded withsodium hydride (4.8 mg, 0.20 mmol) and 2-bromoethanol (14.17 μL, 0.20mmol) and stirred for an additional 8 hours after which 2 additionalequivalents of sodium hydride and 2-bromoethanol were added and thereaction was heated at 50° C. overnight. 29 mg NaH and 86 μL of2-bromoethanol were added and the reaction was heated at 50° C. for 2.5hours. Another 29 mg NaH and 86 L of 2-bromoethanol were added and thereaction was heated at 100° C. for 5 hours. The reaction was quenchedwith methanol and the solvent was evaporated under reduced pressure. Thecrude product was dissolved in DMF, filtered and purified by reversephase preparative chromatography utilizing a gradient of 10-99%acetonitrile in water containing HCl as a modifier to yield2-(4-fluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(85) (43.6 mg, 50%). ¹H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.99 (d,J=2.3 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H),7.38-7.22 (m, 4H), 6.98 (d, J=8.7 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.42(dd, J=7.4, 2.4 Hz, 1H), 3.87 (t, J=5.5 Hz, 2H), 3.57 (t, J=5.5 Hz, 2H)ppm. ESI-MS m/z calc. 436.1, found 437.3 (M+1)+; Retention time: 1.72minutes (3 minutes run).

Example 30 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide(154)

A solution of2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (40mg, 0.11 mmol), 4-fluoro-2-methoxyphenol (12.4 μl, 0.11 mmol), andpotassium carbonate (45 mg, 0.33 mmol), were combined in DMF (0.5 mL)and heated at 90° C. for 16 h. The reaction was filtered, diluted withDMSO (0.5 mL) and purified by reverse phase HPLC using a gradient of25-99% acetonitrile: water and 5 mM HCl as a modifier to provide2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide(154) (17.2 mg, 32%). ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (br s, 1H),10.91 (s, 1H), 7.91 (s, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.26 (dd, J=8.9,5.8 Hz, 1H), 7.20 (dd, J=10.7, 2.9 Hz, 1H), 7.15 (s, 1H), 6.88 (td,J=8.5, 2.9 Hz, 1H), 6.73 (d, J=2.1 Hz, 1H), 6.37 (dd, J=7.2, 2.1 Hz,1H), 3.79 (s, 3H) ppm. ESI-MS m/z calc. 490.08, found 491.3 (M+1)+;Retention time: 1.60 minutes (3 minutes run).

The following products were prepared using a similar reaction sequenceas described above for compound 154.

Cmpd No. Product Alcohol 156N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy- Phenol4,6-bis(trifluoromethyl)benzamide 155 2-(4-fluorophenoxy)-N-(2-oxo-1,2-4-fluorophenol dihydropyridin-4-yl)-4,6-bis(trifluoromethyl) benzamide153 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2- 4-fluoro-2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl) methyl-phenol benzamide152 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2- 2,4-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl) difluorophenol benzamide

Analytical data for the compounds of the present invention is providedbelow in Table 2. Mass Spec (e.g., M+1 data in Table 2), final purityand retention times were determined by reverse phase HPLC using aKinetix C18 column (50 x2.1 mm, 1.7 μm particle) from Phenomenex (pn:00B1-4475-AN)), and a dual gradient run from 1-99% mobile phase Bover 3minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B=CH₃CN (0.05%CF₃CO₂H). Flow rate=2 mL/min, injection volume=3 μL, and columntemperature=50′C.

TABLE 2 Analytical Data LCMS Ret. Cmpd. Time in MS No. minutes (M + 1)¹H-NMR (400 MHz) 1 1.48 325.3 (DMSO-d₆) δ 11.23 (s, 1H), 10.44 (s, 1H),7.62 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (m, 1H), 7.25 (ddd, J = 9.4, 8.6,5.3 Hz, 4H), 7.12 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 1.9Hz, 1H), 6.40 (dd, J = 7.2, 2.0 Hz, 1H) ppm 2 1.72 393.1 (DMSO-d₆) δ11.40 (s, 1H), 10.64 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.83 (dd, J =8.8, 2.3 Hz, 1H), 7.30 (tdd, J = 6.9, 5.9, 3.4 Hz, 5H), 6.99 (d, J = 8.8Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.43 (dd, J = 7.2, 2.0 Hz, 1H) ppm 31.47 325.3 (DMSO-d₆) δ 10.09 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.63(dd, J = 7.6, 1.7 Hz, 1H), 7.50 (m, 2H), 7.23 (m, 3H), 7.08 (m, 2H),6.93 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 9.7 Hz, 1H) ppm 4 1.7 393.1(DMSO-d₆) δ 11.54 (m, 0H), 10.24 (s, 1H), 7.95 (dd, J = 19.3, 2.5 Hz,2H), 7.81 (dd, J = 8.8, 2.1 Hz, 1H), 7.51 (dd, J = 9.7, 2.9 Hz, 1H),7.27 (m, 4H), 7.01 (d, J = 8.6 Hz, 1H), 6.38 (d, J = 9.7 Hz, 1H) ppm 51.72 393.1 (DMSO-d₆) δ 11.31 (s, 1H), 10.63 (s, 1H), 7.85 (d, J = 7.9Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.29 (ddd, J = 8.2, 6.6, 4.6 Hz, 3H),7.21 (m, 2H), 7.14 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.39 (dd, J = 7.2,2.0 Hz, 1H) ppm 6 1.69 393.1 (DMSO-d₆) δ 11.43 (s, 1H), 10.27 (s, 1H),7.90 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.1 Hz,1H), 7.48 (dd, J = 9.7, 2.9 Hz, 1H), 7.27 (dt, J = 12.2, 3.0 Hz, 2H),7.18 (m, 3H), 6.37 (d, J = 9.7 Hz, 1H) ppm 7 1.55 411.17 8 1.52 449.26 91.69 375.1 (DMSO-d₆) δ 11.26 (s, 1H), 10.62 (s, 1H), 7.86 (d, J = 7.9Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.44 (m, 2H), 7.30 (d, J = 7.2 Hz,1H), 7.23 (t, J = 7.4 Hz, 1H), 7.15 (dd, J = 7.1, 6.1 Hz, 3H), 6.75 (d,J = 1.7 Hz, 1H), 6.37 (dd, J = 7.2, 2.0 Hz, 1H) ppm 10 1.79 407.1(DMSO-d₆) δ 11.27 (s, 1H), 10.63 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60(d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.23 (m, 1H), 7.10 (m,2H), 6.97 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.38 (dd, J = 7.2, 2.0 Hz,1H), 2.16 (s, 3H) ppm 11 1.76 389.1 (DMSO-d₆) δ 11.27 (s, 1H), 10.64 (s,1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.30 (m, 3H),7.16 (td, J = 7.4, 1.1 Hz, 1H), 7.00 (m, 2H), 6.75 (d, J = 1.8 Hz, 1H),6.38 (dd, J = 7.2, 2.1 Hz, 1H), 2.17 (s, 3H) ppm 12 1.8 389.1 (DMSO-d₆)δ 11.27 (s, 1H), 10.60 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.59 (d, J =8.0 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.05(d, J = 8.5 Hz, 3H), 6.76 (s, 1H), 6.38 (dd, J = 7.2, 2.0 Hz, 1H), 2.31(s, 3H) ppm 13 1.48 377.1 14 1.55 393.1 15 1.48 359.2 (DMSO-d₆) δ 11.25(s, 1H), 10.48 (s, 1H), 7.65 (t, J = 8.5 Hz, 1H), 7.29 (m, 4H), 7.19 (m,2H), 6.91 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 6.38 (dd, J =7.2, 2.1 Hz, 1H) ppm 16 1.53 389.2 17 1.53 373.2 18 1.43 393.0 19 1.43377.1 20 1.57 373.2 (DMSO-d₆) δ 11.48 (s, 1H), 10.57 (s, 1H), 7.65 (d, J= 8.2 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.30 (dd, J = 8.2, 1.9 Hz, 1H),7.21 (d, J = 9.3 Hz, 1H), 7.10 (m, 2H), 6.83 (d, J = 1.9 Hz, 1H), 6.74(d, J = 1.9 Hz, 1H), 6.45 (dd, J = 7.2, 2.1 Hz, 1H), 2.16 (s, 3H) ppm 211.26 350.1 22 1.3 380.2 23 1.4 364.1 24 1.52 411.2 25 1.28 400.3 26 1.47411.2 (DMSO-d₆) δ 11.30 (s, 1H), 10.71 (d, J = 7.0 Hz, 1H), 8.03 (d, J =2.1 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.39 (m, 4H), 7.03 (d, J = 8.7Hz, 1H), 6.84 (d, J = 21.3 Hz, 1H), 6.46 (m, 1H) ppm 27 1.62 389.3 281.58 389.3 (DMSO-d₆) δ 11.28 (s, 1H), 10.62 (s, 1H), 7.99 (d, J = 2.2Hz, 1H), 7.80 (dd, J = 8.8, 2.2 Hz, 1H), 7.31 (ddd, J = 12.7, 9.2, 4.5Hz, 3H), 7.20 (td, J = 7.4. 1.2 Hz, 1H), 7.12 (m, 1H), 6.81 (dd, J =12.2, 5.3 Hz, 2H), 6.41 (dd, J = 7.2, 2.1 Hz, 1H), 2.15 (s, 3H) ppm 291.57 427.2 (DMSO-d₆) δ 11.29 (s, 1H), 10.62 (s, 1H), 8.02 (d, J = 2.2Hz, 1H), 7.83 (dd, J = 8.8, 2.2 Hz, 1H), 7.69 (dd, J = 8.4, 3.0 Hz, 1H),7.45 (dd, J = 9.1, 5.3 Hz, 1H), 7.40-7.30 (m, 2H), 6.92 (d, J = 8.7 Hz,1H), 6.79 (d, J = 1.9 Hz, 1H), 6.42 (dd, J = 7.2, 2.1 Hz, 1H) ppm 301.56 423.2 31 1.6 407.2 (DMSO-d₆) δ 11.77 (s, 1H), 10.79 (s, 1H), 8.00(d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.8, 2.3 Hz, 1H), 7.45 (d, J = 7.2Hz, 1H), 7.25 (dd, J = 9.3, 3.0 Hz, 1H), 7.16 (m, 2H), 6.95 (d, J = 1.9Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.56 (dd, J = 7.2, 2.0 Hz, 1H), 2.14(s, 3H) ppm 32 1.5 375.2 (DMSO-d₆) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.99(s, 1H), 7.83 (m, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.29 (m, 2H), 7.19 (d,J = 7.6 Hz, 2H), 7.00 (d, J = 8.7 Hz, 1H), 6.79 (s, 1H), 6.41 (m, 1H)ppm 33 1.59 427.1 34 1.51 427.2 35 1.64 405.2 36 1.62 405.2 37 1.61443.1 38 1.56 409.1 39 1.6 423.1 40 1.64 423.1 41 1.54 391.1 42 1.62439.1 43 1.51 393.3 (DMSO-d₆) δ 11.29 (s, 1H), 10.80 (s, 1H), 7.69-7.56(m, 2H), 7.34-7.25 (m, 3H), 7.22- 7.14 (m, 3H), 6.71 (d, J = 2.0 Hz,1H), 6.34 (dd, J = 7.2, 2.1 Hz, 1H) ppm 44 1.83 419.3 (DMSO-d₆) δ 11.43(s, 1H), 10.62 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.9, 2.4Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.22- 7.10 (m, 2H), 7.07-6.95 (m,2H), 6.95-6.80 (m, 2H), 6.45 (dd, J = 7.3, 2.1 Hz, 1H), 4.03 (q, J = 6.9Hz, 2H), 1.33 (t, J = 6.9 Hz, 3H) ppm 45 1.73 405.4 (DMSO-d₆) δ 11.51(s, 1H), 10.66 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.9, 2.4Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.24- 7.10 (m, 2H), 7.08-6.96 (m,2H), 6.92-6.86 (m, 2H), 6.48 (dd, J = 7.2, 2.1 Hz, 1H), 3.77 (s, 3H) ppm46 1.81 419.3 (DMSO-d₆) δ 11.31 (s, 1H), 10.50 (s, 1H), 7.95 (d, J = 2.3Hz, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.31-7.24 (m, 2H), 7.20 (dd, J = 8.3, 1.6 Hz, 1H), 7.04 (td, J = 7.6, 1.6 Hz,1H), 6.89-6.74 (m, 2H), 6.43 (dd, J = 7.2, 2.1 Hz, 1H), 4.02 (q, J = 7.0Hz, 2H), 1.12 (t, J = 6.9 Hz, 3H) ppm 47 1.84 419.3 (DMSO-d₆) δ 11.28(s, 1H), 10.50 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 8.8, 2.3Hz, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.05 (d, J= 2.1 Hz, 1H), 6.85 (dd, J = 8.1, 2.1 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H),6.74 (d, J = 8.7 Hz, 1H), 6.42 (dd, J = 7.3, 2.1 Hz, 1H), 3.72 (s, 3H),2.35 (s, 3H) ppm 48 1.73 423.3 (DMSO-d₆) δ 11.52 (s, 1H), 10.64 (s, 1H),7.97 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 8.9, 2.3 Hz, 1H), 7.41-7.36 (m,1H), 7.36-7.30 (m, 1H), 7.14-7.00 (m, 2H), 6.90 (d, J = 2.0 Hz, 1H),6.83 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 7.2, 2.1 Hz, 1H), 3.79 (s, 3H)ppm 49 1.8 439.2 50 1.89 423.3 51 1.79 427.1 52 1.74 423.3 53 1.94 433.454 1.73 423.3 55 1.74 423.3 (DMSO-d₆) δ 11.50 (s, 1H), 10.70 (s, 1H),7.98 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.8, 2.3 Hz, 1H), 7.43-7.28 (m,2H), 7.10 (dd, J = 12.7, 2.9 Hz, 1H), 6.95-6.83 (m, 3H), 6.48 (dd, J =7.3, 2.1 Hz, 1H), 3.79 (s, 3H) ppm 56 1.8 407.4 57 1.58 423.3 (DMSO-d₆)δ 11.52 (s, 1H), 10.90 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.47 (dd, J =8.7, 2.4 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H),6.84-6.72 (m, 3H), 6.17 (d, J = 7.2 Hz, 1H), 6.06 (d, J = 2.1 Hz, 1H),3.69 (s, 3H) ppm 58 1.81 409.3 59 1.72 423.3 60 2.04 441.3 (DMSO-d₆) δ11.41 (s, 1H), 10.95 (s, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.81 (dd, J =8.8, 2.3 Hz, 1H), 7.29-7.09 (m, 4H), 6.97 (s, 1H), 6.84 (d, J = 8.7 Hz,1H), 2.13 (s, 3H) ppm 61 1.85 421.3 (DMSO-d₆) δ 11.45 (s, 1H), 10.57 (s,1H), 7.97 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.8, 2.3 Hz, 1H), 7.26 (dd,J = 9.4, 2.9 Hz, 1H), 7.22- 7.08 (m, 2H), 6.81 (d, J = 8.7 Hz, 1H), 6.67(d, J = 1.3 Hz, 1H), 6.27 (s, 1H), 2.15 (s, 3H), 2.14 (s, 3H) ppm 621.91 433.4 (DMSO-d₆) δ 11.27 (s, 1H), 10.47 (s, 1H), 7.95 (d, J = 2.2Hz, 1H), 7.77 (dd, J = 8.8, 2.3 Hz, 1H), 7.36-7.23 (m, 3H), 7.23-7.17(m, 1H), 7.08-7.00 (m, 1H), 6.84-6.77 (m, 2H), 6.42 (dd, J = 7.2, 2.0Hz, 1H), 3.90 (t, J = 6.3 Hz, 2H), 1.62-1.38 (m, 2H), 0.67 (t, J = 7.4Hz, 3H) ppm 63 1.81 419.3 (DMSO-d₆) δ 11.38 (s, 1H), 10.62 (s, 1H), 7.96(d, J = 2.2 Hz, 1H), 7.77 (dd, J = 8.8, 2.3 Hz, 1H), 7.35 (d, J = 7.2Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 2.9 Hz, 1H), 6.90- 6.80(m, 2H), 6.74 (d, J = 8.8 Hz, 1H), 6.45 (dd, J = 7.2, 2.0 Hz, 1H), 3.76(s, 3H), 2.10 (s, 3H) ppm 64 1.87 433.4 (DMSO-d₆) δ 11.29 (s, 1H), 10.46(s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.8, 2.0 Hz, 1H),7.40-7.12 (m, 4H), 7.12-6.93 (m, 1H), 6.86-6.73 (m, 2H), 6.42 (dd, J =7.2, 2.1 Hz, 1H), 4.69-4.41 (m, 1H), 1.07 (d, J = 6.0 Hz, 6H) ppm 651.74 409.3 (DMSO-d₆) δ 11.30 (s, 1H), 10.62 (s, 1H), 8.02 (d, J = 2.2Hz, 1H), 7.84 (dd, J = 8.8. 2.3 Hz, 1H), 7.65 (dd, J = 7.9, 1.5 Hz, 1H),7.54- 7.39 (m, 1H), 7.39-7.24 (m, 3H), 6.91 (d, J = 8.7 Hz, 1H), 6.79(d, J = 1.8 Hz, 1H), 6.41 (dd, J = 7.2, 2.1 Hz, 1H) ppm 66 1.64 393.1 671.46 359.2 68 1.57 373.1 69 1.46 377.1 70 1.52 389.1 71 1.46 389.2 721.93 459.3 (DMSO-d₆) δ 11.29 (s, 1H), 10.62 (s, 1H), 8.02 (d, J = 2.3Hz, 1H), 7.86 (dd, J = 8.7, 2.4 Hz, 1H), 7.58-7.40 (m, 2H), 7.40-7.21(m, 3H), 7.11 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 6.38 (dd, J= 7.2, 2.1 Hz, 1H) ppm 73 1.83 441.5 (DMSO-d₆) δ 11.77 (s, 1H), 10.79(s, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 8.9, 2.4 Hz, 1H),7.49-6.99 (m, 7H), 6.94 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 7.2, 2.1 Hz,1H) ppm 74 1.75 443.5 (DMSO-d₆) δ 11.55 (s, 1H), 10.93 (s, 1H),7.83-7.67 (m, 3H), 7.61-7.45 (m, 3H), 7.33 (d, J = 7.0 Hz, 1H), 6.88 (d,J = 8.5 Hz, 1H), 6.11-5.98 (m, 2H) ppm 75 1.83 459.3 (DMSO-d₆) δ 11.28(s, 1H), 10.63 (s, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.7, 2.4Hz, 1H), 7.60-7.54 (m, 1H), 7.54-7.43 (m, 1H), 7.43-7.34 (m, 1H),7.34-7.28 (m, 2H), 7.05 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H),6.38 (dd, J = 7.2, 2.1 Hz, 1H) ppm 76 1.76 441.5 (DMSO-d₆) δ 11.56 (s,1H), 10.69 (s, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.8, 2.4 Hz,1H), 7.47-6.97 (m, 6H), 6.94 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 2.0 Hz,1H), 6.49 (dd, J = 7.2, 2.1 Hz, 1H) ppm 77 1.78 427.3 (DMSO-d₆) δ 11.29(s, 1H), 10.64 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.71-7.61 (m, 2H),7.39-7.26 (m, 3H), 7.13-7.06 (m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.39(dd, J = 7.2, 2.1 Hz, 1H) ppm 78 1.73 409.3 (DMSO-d₆) δ 11.28 (s, 1H),10.62 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.48(m, 2H), 7.30 (m, 2H), 7.13 (m, 2H), 6.73 (s, 1H), 6.36 (dd, J = 7.2.2.0 Hz, 1H) ppm 79 1.8 459.5 80 1.74 459.3 81 1.65 423.3 82 1.71 441.383 1.68 441.3 84 1.67 423.3 (DMSO-d₆) δ 11.34 (s, 1H), 10.67 (s, 1H),7.83 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.32 (m, 2H), 7.09(dd, J = 12.7, 3.0 Hz, 1H), 6.98 (s, 1H), 6.87 (m, 1H), 6.80 (d, J = 1.7Hz, 1H), 6.42 (dd, J = 7.2, 2.0 Hz, 1H), 3.79 (s, 3H) ppm 85 1.72 437.3(DMSO-d₆) δ 10.63 (s, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.8,2.4 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.38-7.22 (m, 4H), 6.98 (d, J =8.7 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 7.4, 2.4 Hz, 1H),3.87 (t, J = 5.5 Hz, 2H), 3.57 (t, J = 5.5 Hz, 2H) ppm 86 1.89 421.2(DMSO-d₆) δ 11.66 (s, 1H), 9.91 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.85(dd, J = 8.8, 2.4 Hz, 1H), 7.45-7.28 (m, 4H), 7.20 (td, J = 8.5, 3.1 Hz,1H), 6.78 (d, J = 8.8 Hz, 1H), 2.17 (s, 3H), 1.96 (s, 3H) ppm 87 1.67423.1 88 1.59 443.5 (DMSO-d₆) δ 7.87 (d, J = 7.9 Hz, 1H), 7.59 (d, J =7.6 Hz, 1H), 7.37-7.25 (m, 3H), 7.24- 7.16 (m, 2H), 7.07 (s, 1H), 6.73(s, 1H), 6.37 (d, J = 6.9 Hz, 1H) ppm 89 1.58 473.3 (DMSO-d₆) δ 11.28(s, 1H), 10.62 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.2 Hz,1H), 7.31 (d, J = 6.9 Hz, 1H), 7.27-7.16 (m, 2H), 7.07 (s, 1H), 6.98 (d,J = 8.9 Hz, 1H), 6.76 (s, 1H), 6.38 (d, J = 7.1 Hz, 1H), 3.84 (s, 3H)ppm 90 1.76 429.3 91 1.98 417.4 92 1.81 425.2 93 1.99 417.4 94 1.83367.3 95 1.5 325.5 (DMSO-d₆) δ 11.24 (s, 1H), 10.49 (s, 1H), 7.54 (dd, J= 8.4, 3.2 Hz, 1H), 7.43-7.32 (m, 3H), 7.28 (d, J = 7.2 Hz, 1H), 7.12(t, J = 7.4 Hz, 1H), 7.05 (dd, J = 9.0, 4.5 Hz, 1H), 7.03- 6.97 (m, 2H),6.71 (d, J = 1.9 Hz, 1H), 6.37 (dd, J = 7.2, 2.1 Hz, 1H) ppm 96 1.69365.3 97 1.66 397.3 (DMSO-d₆) δ 11.23 (s, 1H), 10.46 (s, 1H), 7.50 (dd,J = 8.4, 3.2 Hz, 1H), 7.40-7.32 (m, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.00(dd, J = 9.1, 4.4 Hz, 1H), 6.98-6.92 (m, 4H), 6.72 (d, J = 1.8 Hz, 1H),6.37 (dd, J = 7.2, 2.0 Hz, 1H), 1.24 (s, 9H) ppm 98 1.61 369.3 99 1.74367.3 100 1.73 383.3 101 1.68 409.3 102 1.53 383.3 103 1.61 389.5(DMSO-d₆) δ 11.26 (s, 1H), 10.50 (s, 1H), 7.52 (dd, J = 8.4, 3.2 Hz,1H), 7.36-7.27 (m, 2H), 7.17 (dd, J = 6.0, 3.0 Hz, 2H), 6.97 (dd, J =9.0, 3.0 Hz, 1H), 6.81-6.73 (m, 2H), 6.43-6.36 (m, 1H), 3.77 (s, 3H) ppm104 1.54 355.5 105 1.85 367.3 106 1.52 407.1 107 1.74 423.3 (DMSO-d₆) δ11.27 (s, 1H), 10.49 (s, 1H), 7.52 (dd, J = 8.4, 3.2 Hz, 1H), 7.41-7.23(m, 2H), 7.13-7.00 (m, 4H), 6.94 (dd, J = 9.1, 4.3 Hz, 1H), 6.75 (d, J =2.1 Hz, 1H), 6.39 (dd, J = 7.2, 2.1 Hz, 1H), 4.73 (q, J = 8.9 Hz, 2H)ppm 108 1.78 395.3 (DMSO-d₆) δ 11.28 (s, 1H), 10.48 (s, 1H), 7.49 (dd, J= 8.4, 3.3 Hz, 1H), 7.40-7.23 (m, 2H), 7.04-6.97 (m, 2H), 6.97-6.91 (m,2H), 6.91-6.86 (m, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.40 (dd, J = 7.2, 2.1Hz, 1H), 3.77 (d, J = 7.0 Hz, 2H), 1.28-1.07 (m, 1H), 0.62-0.42 (m, 2H),0.39-0.20 (m, 2H) ppm 109 1.76 411.2 (DMSO-d₆) δ 11.39 (s, 1H), 10.60(s, 1H), 7.88-7.79 (m, 1H), 7.61 (dd, J = 8.4, 2.9 Hz, 1H), 7.33 (d, J =7.2 Hz, 1H), 7.31-7.16 (m, 3H), 6.74 (d, J = 2.1 Hz, 1H), 6.39 (dd, J =7.3, 2.1 Hz, 1H) ppm 110 1.52 457.3 (DMSO-d₆) δ 11.48 (s, 1H), 10.66 (s,1H), 7.86 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.47 (d, J =8.7 Hz, 1H), 7.41 (d, J = 11.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.03(s, 1H), 6.83 (s, 1H), 6.45 (d, J = 7.1 Hz, 1H), 3.89 (s, 3H) ppm 1111.62 473.3 (DMSO-d₆) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J = 7.9Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.39-7.27 (m, 2H), 7.17 (dd, J =10.7, 2.8 Hz, 1H), 6.88 (dd, J = 11.3, 5.7 Hz, 1H), 6.81 (s, 1H), 6.75(s, 1H), 6.43 (d, J = 7.1 Hz, 1H), 3.73 (s, 3H) ppm 112 1.66 457.5(DMSO-d₆) δ 11.29 (s, 1H), 10.66 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.57(d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.1 Hz, 1H), 7.24 (dd, J = 9.2, 2.7Hz, 1H), 7.17-7.04 (m, 2H), 6.90 (s, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.38(dd, J = 7.2, 2.0 Hz, 1H), 2.15 (s, 3H) ppm 113 1.53 393.1 (DMSO-d₆) δ11.32 (s, 1H), 10.57 (s, 1H), 7.95 (s, 1H), 7.34-7.24 (m, 3H), 7.22-7.15(m, 3H), 6.74 (s, 1H), 6.38 (d, J = 7.2 Hz, 1H) ppm 114 1.57 423.3(DMSO-d₆) δ 11.27 (s, 1H), 10.49 (s, 1H), 7.90 (br s, 1H), 7.32 (d, J =7.2 Hz, 1H), 7.28 (dd, J = 8.9, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz,1H), 6.89-6.82 (m, 2H), 6.77 (s, 1H), 6.39 (dd, J = 7.2, 2.1 Hz, 1H),3.76 (s, 3H) ppm 115 1.52 423.3 (DMSO-d₆) δ 11.41 (s, 1H), 10.57 (s,1H), 7.94 (s, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.30- 7.12 (m, 3H), 6.96(d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.40 (d, J = 7.1 Hz, 1H), 3.83 (s,3H) ppm 116 1.85 369.1 (DMSO-d₆) δ 11.41 (s, 1H), 10.35 (s, 1H), 7.71(d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.39 (dd, J = 15.4, 7.6 Hz, 2H), 6.83(d, J = 1.7 Hz, 1H), 6.43 (dd, J = 7.2, 2.0 Hz, 1H), 4.18 (t, J = 6.4Hz, 2H), 1.75 (td, J = 13.4, 6.6 Hz, 1H), 1.62 (q, J = 6.5 Hz, 2H), 0.90(t, J = 8.0 Hz, 6H) ppm 117 1.58 355.2 118 1.77 393.3 119 1.62 367.2 1201.72 381.2 121 1.33 383.2 122 1.55 353.2 123 1.57 409.2 124 1.72 381.2125 1.6 379.2 126 1.5 389.2 127 1.72 393.2 128 1.85 381.1 (DMSO-d₆) δ11.36 (s, 1H), 10.32 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H),7.36 (dd, J = 14.6, 7.6 Hz, 2H), 6.81 (s, 1H), 6.42 (dd, J = 7.2, 2.0Hz, 1H), 4.68 (m, 1H), 1.88 (m, 2H), 1.44 (m, 8H) ppm 129 1.47 375.2 1301.64 381.3 131 1.52 355.3 132 1.56 395.2 133 1.5 409.3 134 1.64 381.3135 1.54 379.3 136 1.71 397.2 137 1.68 397.2 138 1.58 411.1 139 1.56425.1 140 1.7 397.2 141 1.78 432.3 142 1.78 432.5 (DMSO-d₆) δ 10.12 (s,1H), 8.45 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H),7.66 (d, J = 8.1 Hz, 1H), 7.44 (m, 3H), 7.32 (d, J = 1.8 Hz, 1H), 6.33(d, J = 9.6 Hz, 1H), 1.30 (s, 9H) ppm 143 1.58 410.3 (DMSO-d₆) δ 11.41(s, 1H), 10.62 (s, 1H), 8.56 (d, J = 2.7 Hz, 1H), 7.92 (d, J = 8.7 Hz,1H), 7.76 (d, J = 8.2 Hz, 1H), 7.62 (dd, J = 8.7, 2.7 Hz, 1H), 7.51 (m,2H), 7.32 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.39 (dd, J =7.2, 2.1 Hz, 1H) ppm 144 1.67 444.3 (DMSO-d₆) δ 11.29 (s, 1H), 10.69 (s,1H), 8.57 (d, J = 2.8 Hz, 1H), 7.94 (t, J = 8.8 Hz, 2H), 7.82 (d, J =8.2 Hz, 1H), 7.76 (s, 1H), 7.62 (dd, J = 8.7, 2.9 Hz, 1H), 7.29 (d, J =7.0 Hz, 1H), 6.67 (s, 1H), 6.33 (d, J = 7.4 Hz, 1H) ppm 145 1.64 444.3146 0.98 390.2 147 0.97 390.2 148 1.87 446.1 (DMSO-d₆) δ 10.49 (s, 1H),8.45 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.1 Hz,1H), 7.57 (d, J = 7.4 Hz, 1H), 7.49 (dd, J = 8.1, 1.8 Hz, 1H), 7.42 (dd,J = 8.6, 2.8 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 6.70 (d, J = 2.3 Hz,1H), 6.38 (dd, J = 7.4, 2.3 Hz, 1H), 3.33 (s, 3H), 1.29 (s, 9H) ppm 1491.85 446.3 (DMSO-d₆) δ 10.15 (s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.10 (d,J = 2.7 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H),7.48 (dd, J = 8.1, 1.7 Hz, 1H), 7.39 (m, 2H), 7.32 (d, J = 1.6 Hz, 1H),6.37 (d, J = 9.7 Hz, 1H), 3.39 (s, 3H), 1.30 (s, 9H) ppm 150 0.95 390.3151 0.98 406.2 152 1.57 479.3 (DMSO-d₆) δ 11.37 (brs, 1H), 10.96 (s,1H), 8.02 (s, 1H), 7.59-7.52 (m, 2H), 7.41 (td, J = 9.2, 5.5 Hz, 1H),7.34 (d, J = 7.1 Hz, 1H), 7.24-7.15 (m, 1H), 6.70 (d, J = 2.0 Hz, 1H),6.33 (dd, J = 7.2, 2.1 Hz, 1H) ppm 153 1.64 475.3 (DMSO-d₆) δ 11.36(brs, 1H), 10.94 (s, 1H), 7.95 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.29-7.24 (m, 2H), 7.21-7.11 (m, 2H), 6.70 (d, J = 2.0 Hz, 1H), 6.33 (dd, J =7.2, 2.1 Hz, 1H), 2.16 (s, 3H) ppm 154 1.6 491.3 (DMSO-d₆) δ 11.38 (brs, 1H), 10.91 (s, 1H), 7.91 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.26 (dd,J = 8.9, 5.8 Hz, 1H), 7.20 (dd, J = 10.7, 2.9 Hz, 1H), 7.15 (s, 1H),6.88 (td, J = 8.5, 2.9 Hz, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.37 (dd, J =7.2, 2.1 Hz, 1H), 3.79 (s, 3H) ppm 155 1.58 461.3 (DMSO-d₆) δ 11.34 (brs, 1H), 10.91 (s, 1H), 7.99 (s, 1H), 7.47 (s, 1H), 7.38-7.28 (m, 3H),7.29-7.24 (m, 2H), 6.69 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 7.2, 2.1 Hz,1H) ppm 156 1.55 443.1 (DMSO-d₆) δ 11.34 (br s, 1H), 10.92 (s, 1H), 7.99(d, J = 1.5 Hz, 1H), 7.53-7.43 (m, 3H), 7.35-7.26 (m, 2H), 7.20 (d, J =7.6 Hz, 2H), 6.69 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 7.2, 2.1 Hz, 1H)ppm 157 1.32 423.2 (DMSO-d₆) δ 11.44 (s, 1H), 10.66 (s, 1H), 7.86 (d, J= 7.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.41-7.27 (m, 2H), 7.24-7.12(m, 1H), 7.12-7.07 (m, 1H), 7.04 (s, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.43(dd, J = 7.3, 2.2 Hz, 1H), 4.47 (s, 2H) ppm 158 1.7 423.3 (DMSO-d₆) δ11.33 (s, 1H), 10.58 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.7Hz, 1H), 7.37-7.26 (m, 2H), 7.17 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (m,3H), 6.42 (dd, J = 7.2, 2.0 Hz, 1H), 3.76 (s, 3H) ppm 159 1.83 423.3(DMSO-d₆) δ 11.52 (s, 1H), 10.49 (s, 1H), 10.04 (s, 1H), 7.84 (d, J =8.2 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.33-7.23 (m, 2H), 7.05-6.91 (m,2H), 6.91-6.79 (m, 2H), 6.61 (dd, J = 7.4, 2.4 Hz, 1H), 4.96 (s, 2H) ppm160 1.45 451.2

Assays for Detecting and Measuring Na_(V) Inhibition Properties ofCompounds

E-VIPR Optical Membrane Potential Assay Method with ElectricalStimulation

Sodium channels are voltage-dependent proteins that can be activated byinducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use are described inIon Channel Assay Methods PCT/US01/21652, herein incorporated byreference and are referred to as E-VIPR. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, and adevice for inserting electrodes in well. Under integrated computercontrol, this instrument passes user-programmed electrical stimulusprotocols to cells within the wells of the microtiter plate.

24 hours before the assay on E-VIPR, HEK cells expressing humanNa_(V)1.8 were seeded in 384-well poly-lysine coated plates at15,000-20,000 cells per well. HEK cells were grown in media (exactcomposition is specific to each cell type and NaV subtype) supplementedwith 10% FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-071) and 1%Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells weregrown invented cap flasks, in 90% humidity and 5% CO₂.

Reagents and Solutions

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: 384-well round bottom plate, e.g. Corning 384-wellPolypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plate, e.g. Greiner#781091-1B

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC in H₂O

Bath1 buffer: Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous), 1mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L), HEPES 10 mM (2.38g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Sodium Chloride 160 mM(9.35 g/L).

Hexyl Dye Solution: Bath1 Buffer+0.5%-cyclodextrin (made this prior touse, Sigma #C4767), 8 μM CC2-DMPE+2.5 M DiSBAC₆(3). To make the solutionadded volume of 10% Pluronic F127 stock equal to volumes ofCC2-DMPE+DiSBAC₆(3). The order of preparation was first mixing Pluronicand CC2-DMPE, then adding DiSBAC₆(3) while vortexing, then addingBath1+β-Cyclodextrin.

Assay Protocol

1) Pre-spotted compounds (in neat DMSO) into compound plates. Vehiclecontrol (neat DMSO), the positive control (20 mM DMSO stock tetracaine,125 μM final in assay) and test compounds were added to each well at160× desired final concentration in neat DMSO. Final compound platevolume was 80 μL (80-fold intermediate dilution from 1 μL DMSO spot;160-fold final dilution after transfer to cell plate). Final DMSOconcentration for all wells in assay was 0.625%.

2) Prepared Hexyl Dye Solution.

3) Prepared cell plates. On the day of the assay, medium was aspiratedand cells were washed three times with 100 μL of Bath1 Solution,maintaining 25 μL residual volume in each well.

4) Dispensed 25 μL per well of Hexyl Dye Solution into cell plates.Incubated for 20-35 minutes at room temp or ambient conditions.

5) Dispensed 80 μL per well of Bath1 into compound plates. AcidYellow-17 (1 mM) was added and Potassium Chloride was altered from 4.5to 20 mM depending on the NaV subtype and assay sensitivity.

6) Washed cell plates three times with 100 μL per well of Bath1, leaving25 μL of residual volume. Then transferred 25 uL per well from CompoundPlates to Cell Plates. Incubated for 20-35 minutes at room temp/ambientcondition.

7) Read Plate on E-VIPR. Used the current-controlled amplifier todeliver stimulation wave pulses for 10 seconds and a scan rate of 200Hz. A pre-stimulus recording was performed for 0.5 seconds to obtain theun-stimulated intensities baseline. The stimulatory waveform wasfollowed by 0.5 seconds of post-stimulation recording to examine therelaxation to the resting state.

Data Analysis

Data was analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} \right)}$

The data was further reduced by calculating the initial (R_(i)) andfinal (R_(f)) ratios. These were the average ratio values during part orall of the pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R□□=R_(f)/R_(i) wasthen calculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofa compound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls werecalculated as above. The compound antagonist activity A is defined as:

${A = {\frac{R - P}{N - P}*100}}.$

where R is the ratio response of the test compound

Electrophysiology Assays for Na_(V) Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)were visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modewas used to assess the compound's IC₅₀ holding the cells at −60 mV. Inaddition, the “current clamp” mode was employed to test the efficacy ofthe compounds in blocking action potential generation in response tocurrent injections. The results of these experiments contributed to thedefinition of the efficacy profile of the compounds.

The exemplified compounds in Table 1 herein are active against Na_(V)1.8sodium channels as measured using the assays described herein and aspresented in Table 3 below.

TABLE 3 Nav1.8 IC₅₀ activity Cmpd. No Nav1.8 IC₅₀ (μM) 1 1.09 2 0.054 313.5 4 0.35 5 0.039 6 0.245 7 0.05 8 0.33 9 0.093 10 0.014 11 0.056 120.106 13 0.106 14 0.065 15 0.076 16 0.014 17 1.8 18 12 19 6 20 0.03 210.843 22 0.1 23 1.5 24 0.058 25 1.1 26 9.65 27 0.34 28 0.044 29 0.028 300.011 31 0.017 32 0.205 33 0.095 34 12 35 0.47 36 0.101 37 0.051 380.069 39 0.69 40 0.04 41 0.26 42 0.068 43 0.38 44 0.02 45 0.064 46 0.06447 0.135 48 2.7 49 0.024 50 0.019 51 0.087 52 0.094 53 0.047 54 0.03 550.07 56 0.069 57 6.9 58 0.054 59 0.032 60 0.126 61 0.113 62 0.034 630.018 64 0.108 65 0.107 66 0.037 67 0.069 68 0.03 69 0.112 70 0.013 710.092 72 0.013 73 0.035 74 5.175 75 0.051 76 0.054 77 0.029 78 0.031 790.011 80 0.105 81 0.026 82 0.036 83 0.046 84 0.046 85 2.8 86 3.55 870.027 88 0.012 89 0.016 90 0.026 91 0.42 92 0.135 93 1.45 94 1.4 95 3.4596 0.4 97 0.745 98 0.3 99 5.15 100 0.155 101 0.12 102 17.1 103 0.33 1041.15 105 3.55 106 0.099 107 0.39 108 0.285 109 0.019 110 0.89 111 0.003112 0.016 113 0.006 114 0.001 115 0.007 116 0.488 117 1.145 118 0.765119 14 120 0.15 121 19 122 4.2 123 0.355 124 0.485 125 17.5 126 1.4 1271.3 128 0.56 129 0.94 130 5.1 131 1.5 132 0.33 133 5.8 134 21 135 1.65136 2.6 137 12.65 138 1.45 139 3.05 140 15 141 0.078 142 0.653 143 3.35144 0.615 145 5 146 4.6 147 3.8 148 0.45 149 1.65 150 6.6 151 8.4 1520.044 153 0.01 154 0.005 155 0.011 156 0.052 157 0.058 158 0.002 159 2.6160 1.39

IonWorks assays. This assay was performed to determine the activity forthe compounds of the present invention against non Na_(V)1.8 channels.Sodium currents were recorded using the automated patch clamp system,IonWorks (Molecular Devices Corporation, Inc.). Cells expressing Na_(V)subtypes were harvested from tissue culture and placed in suspension at0.5-4 million cells per mL Bath1. The IonWorks instrument measuredchanges in sodium currents in response to applied voltage clampsimilarly to the traditional patch clamp assay, except in a 384-wellformat. Using the IonWorks, dose-response relationships were determinedin voltage clamp mode by depolarizing the cell from the experimentspecific holding potential to a test potential of about 0 mV before andfollowing addition of the test compound. The influence of the compoundon currents were measured at the test potential.

Microsomal Stability Assay. Compounds were incubated at 37° C. andshaken for 30 minutes in a phosphate buffered solution with either rator human liver microsomes and the cofactor NADPH. A time zero controlwas similarly prepared, however with NADPH excluded. The finalincubation concentrations were 1 uM substrate (0.2% DMSO), 0.5 mg/mLliver microsome, 2 mM NADPH, and 0.1 M phosphate. Reactions werequenched and proteins precipitated with the addition of 2 volumeequivalents of ice cold acetonitrile containing an internal standard.Following a centrifugation step, aliquots from the quenched incubationswere further diluted with 4 volume equivalents of a 50% aqueous methanolsolution and then subjected to LC/MS/MS analysis for quantitation ofparent compound. Microsome stability values were calculated as thepercent of substrate remaining after 30 minutes referenced against thetime zero control.

Microsomal stability in rat and human liver microsomes were determinedfor selected compounds of the present invention using the above assay.Table 4 provides the human liver microsomes (“HLM”) and rat livermicrosomes (“RLM”) stability data as the percent of compound remainingafter 30 minutes referenced against the time zero control.

TABLE 4 HLM and RLM Stability Data HLM RLM Cmpd. (% remaining @ (%remaining @ No 30 minutes) 30 minutes) 2 100 104 7 97 99 8 90 86 10 9382 20 104 88 28 79 70 29 107 107 30 76 78 31 92 91 33 100 110 37 100 9744 93 84 66 100 106 68 98 72 72 100 95.5 75 90 95 76 97 93 79 103 100 82101 98 88 100 102 90 101 104 101 97 89 109 103 100 111 91 90 113 105 102114 91 82 115 102 95 120 87 79 123 103 98 142 38 50 152 103 100 157101.5 102

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

1-33. (canceled)
 34. A process for preparing a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H,halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen and wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; R² is H, halogen, CN, or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up totwo non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—;R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁴ is H, halogen, CN, orC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—; R⁵ is H, halogen, CN, or —X—R^(X); R⁶ is H, halogen,CN, or —X—R^(X); R^(6′) is H, halogen, CN, or —X—R^(X); R^(6′) is H,halogen, CN, or —X—R^(X); R⁷ is H, halogen, CN, or —X—R^(X); X is a bondor C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—; and R^(X) is absent, H, or C₃-C₈ cycloaliphatic,wherein up to two non-adjacent CH₂ units of said C₃-C₈ cycloaliphaticmay be replaced with —O— and said C₃-C₈ cycloaliphatic is substitutedwith 0-3 substituents selected from halogen and C₁-C₄ alkyl; comprising:transforming a compound of formula F

to the compound of formula I; and optionally, treating the compound offormula I with an acid or a first base to afford the pharmaceuticallyacceptable salt.
 35. The process of claim 34, wherein transforming thecompound of formula F to the compound of formula I comprises treatingthe compound of formula F with TMSI or HBr.
 36. The process of claim 34,wherein the compound of formula F is obtained by treating a compound offormula G

with 2-methoxypyridin-4-amine in the presence of a coupling agent and asecond base to afford the compound of formula F.
 37. The process ofclaim 35, wherein the compound of formula F is obtained by treating acompound of formula G

with 2-methoxypyridin-4-amine in the presence of a coupling agent and asecond base to afford the compound of formula F.
 38. The process ofclaim 34, wherein: R¹ is H; R² is H; R³ is CF₃; R⁴ is H; R⁵ is CH₃;R^(5′) is H; R⁶ is H; R^(6′) is H; and R⁷ is F.
 39. The process of claim34, wherein: R¹ is H; R² is CF₃; R³ is H; R⁴ is H; R⁵ is H; R^(5′) is H;R⁶ is H; R^(6′) is H; and R⁷ is F.
 40. The process of claim 35, wherein:R¹ is H; R² is H; R³ is CF₃; R⁴ is H; R⁵ is CH₃; R^(5′) is H; R⁶ is H;R^(6′) is H; and R⁷ is F.
 41. The process of claim 35, wherein: R¹ is H;R² is CF₃; R³ is H; R⁴ is H; R⁵ is H; R^(5′) is H; R⁶ is H; R^(6′) is H;and R⁷ is F.
 42. The process of claim 36, wherein: R¹ is H; R² is H; R³is CF₃; R⁴ is H; R⁵ is CH₃; R^(5′) is H; R⁶ is H; R^(6′) is H; and R⁷ isF.
 43. The process of claim 36, wherein: R¹ is H; R² is CF₃; R³ is H; R⁴is H; R⁵ is H; R^(5′) is H; R⁶ is H; R^(6′) is H; and R⁷ is F.
 44. Theprocess of claim 37, wherein: R¹ is H; R² is H; R³ is CF₃; R⁴ is H; R⁵is CH₃; R^(5′) is H; R⁶ is H; R^(6′) is H; and R⁷ is F.
 45. The processof claim 37, wherein: R¹ is H; R² is CF₃; R³ is H; R⁴ is H; R⁵ is H;R^(5′) is H; R⁶ is H; R^(6′) is H; and R⁷ is F.
 46. A compound offormula F

wherein: R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkylis substituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—; R² is H, halogen,CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkylmay be replaced with —O—; R³ is H, halogen, CN, or C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—; R⁴is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁵ is H, halogen, CN, or—X—R^(X); R^(5′) is H, halogen, CN, or —X—R^(X); R⁶ is H, halogen, CN,or —X—R^(X); R^(6′) is H, halogen, CN, or —X—R^(X); R⁷ is H, halogen,CN, or —X—R^(X); X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; and R^(X) is absent, H, orC₃-C₈ cycloaliphatic, wherein up to two non-adjacent CH₂ units of saidC₃-C₈ cycloaliphatic may be replaced with —O— and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl.
 47. The compound of claim 46, wherein: R¹ is H;R² is H; R³ is CF₃; R⁴ is H; R⁵ is CH₃; R^(5′) is H; R⁶ is H; R^(6′) isH; and R⁷ is F.
 48. The compound of claim 46, wherein: R¹ is H; R² isCF₃; R³ is H; R⁴ is H; R⁵ is H; R^(5′) is H; R⁶ is H; R^(6′) is H; andR⁷ is F.
 49. A compound of formula G

wherein: R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkylis substituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—; R² is H, halogen,CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkylmay be replaced with —O—; R³ is Cl, CF₃, or CF₂CF₃; R⁴ is H, halogen,CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkylmay be replaced with —O—; R⁵ is H, halogen, CN, or —X—R^(X); R^(5′) isH, halogen, CN, or —X—R^(X); R⁶ is H, halogen, CN, or —X—R^(X); R^(6′)is H, halogen, CN, or —X—R^(X); R⁷ is halogen; X is a bond or C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen, whereinup to two non-adjacent CH₂ units of said C₁-C₆ alkyl may be replacedwith —O—; and R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up totwo non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replacedwith —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl.
 50. The compound ofclaim 49, wherein: R¹ is H; R² is H; R³ is CF₃; R⁴ is H; R⁵ is CH₃;R^(5′) is H; R⁶ is H; R^(6′) is H; and R⁷ is F.